Clark Lantz

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Scholarly Contributions

Chapters

• Lantz, R. C., & Vera, J. (2016). Toxicity of Airborne Metals. In Comprehensive Toxicology.
• Sherwood, C. L., & Lantz, R. C. (2015). Lung Cancer and Other Pulmonary Diseases. In Arsenic - Exposure Sources, Health Risks and Mechanisms of Toxicity(pp 137 - 162). John Wiley and Sons.
• Sarihan, P., & Lantz, R. C. (2008). THE EFFECT OF ARSENIC ON SMOOTH MUSCLE ACTIN IN THE LUNG. In Honors Thesis. The University of Arizona.

Journals/Publications

• Recio-vega, R., Olivas-calderon, E., Michel-ramirez, G., Lantz, R. C., Hernandez-gonzalez, S., Gandolfi, A. J., & Amistadi, M. K. (2021). Association between the polymorphism of three genes involved in the methylation and efflux of arsenic (As3MT, MRP1, and P-gp) with lung cancer in a Mexican cohort.. Journal of applied toxicology : JAT, 41(9), 1357-1366. doi:10.1002/jat.4127
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  Lung cancer is the most common neoplasm and the primary cause-related mortality in developed and in most of nondeveloped countries. Epidemiological studies have demonstrated that even at low arsenic doses, the lungs are one of the main target organs and that chronic arsenic exposure has been associated with an increase in lung cancer development. Among the risk factors for cancer, arsenic methylation efficiency (As3MT) and the clearance of arsenic from cells by two members of the ATP-binding cassette (ABC) transporter family (multidrug resistance protein 1 [MRP1] and P-glycoprotein [P-gp]) play an important role in processing of arsenic and decreasing its intracellular levels. This study aimed to evaluate the association between chronic exposure to arsenic with polymorphism of three proteins involved in arsenic metabolism and efflux of the metalloid in subjects with lung cancer. Polymorphism in As3MT, MRP1, and P-gp modified the arsenic metabolism increasing significantly the AsV urinary levels. A significant association between MRP1 polymorphisms with an increase in the risk for cancer was found. The high inorganic arsenic urinary levels registered in the studied subjects suggest a reduction in the efficiency of As3MT, MRP1, and P-gp firstly because of gene polymorphisms and secondarily because of high internal inorganic arsenic levels. MRP1 polymorphism was associated with a twofold increase in the risk of lung cancer.
• Vega-millan, C. B., Rourke, M. K., O'rourke, M. K., Meza-montenegro, M. M., Meza-figueroa, D., Meza-escalante, E. R., Lantz, R. C., Garcia-rico, L., Furlong, M., Devora-figueroa, A. G., Burgess, J. L., Beamer, P. I., & Balderas-cortes, J. D. (2021). Inflammation biomarkers associated with arsenic exposure by drinking water and respiratory outcomes in indigenous children from three Yaqui villages in southern Sonora, México. Environmental Science and Pollution Research, 28(26), 1-12. doi:10.1007/s11356-021-13070-x
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  Environmental arsenic exposure in adults and children has been associated with a reduction in the expression of club cell secretory protein (CC16) and an increase in the expression of matrix metalloproteinase-9 (MMP-9), both biomarkers of lung inflammation and negative respiratory outcomes. The objectives of this study were to determine if the levels of serum CC16 and MMP-9 and subsequent respiratory infections in children are associated with the ingestion of arsenic by drinking water. This cross-sectional study included 216 children from three Yaqui villages, Potam, Vicam, and Cocorit, with levels of arsenic in their ground water of 70.01 ± 21.85, 23.3 ± 9.99, and 11.8 ± 4.42 μg/L respectively. Total arsenic in water and urine samples was determined by inductively coupled plasma/optical emission spectrometry. Serum was analyzed for CC16 and MMP-9 using ELISA. The children had an average urinary arsenic of 79.39 μg/L and 46.8 % had levels above of the national concern value of 50 μg/L. Increased arsenic concentrations in drinking water and average daily arsenic intake by water were associated with decreased serum CC16 levels (β = - 0.12, 95% CI - 0.20, - 0.04 and β = - 0.10, 95% CI - 0.18, - 0.03), and increased serum MMP-9 levels (β = 0.35, 95% CI 0.22, 0.48 and β = 0.29, 95% CI 0.18, 0.40) at significant levels (P < 0.05). However, no association was found between levels of these serum biomarkers and urinary arsenic concentrations. In these children, reduced serum CC16 levels were significantly associated with increased risk of respiratory infections (OR = 0.34, 95% CI 0.13, 0.90). In conclusion, altered levels of serum CC16 and MMP-9 in the children may be due to the toxic effects of arsenic exposure through drinking water.
• Witten, M. L., Lantz, R. C., Cromey, D., Chen, Y., & Chau, B. (2021). Lung developmental is altered after inhalation exposure to various concentrations of calcium arsenate.. Toxicology and applied pharmacology, 432, 115754. doi:10.1016/j.taap.2021.115754
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  Exposure to dust from active and abandoned mining operations may be a very significant health hazard, especially to sensitive populations. We have previously reported that inhalation of real-world mine tailing dusts during lung development can alter lung function and structure in adult male mice. These real-world dusts contain a mixture of metal(loid)s, including arsenic. To determine whether arsenic in inhaled dust plays a role in altering lung development, we exposed C57Bl/6 mice to a background dust (0 arsenic) or to the background dust containing either 3% or 10% by mass, calcium arsenate. Total level of exposure was kept at 100 μg/m3. Calcium arsenate was selected since arsenate is the predominant species found in mine tailings. We found that inhalation exposure during in utero and postnatal lung development led to significant increases in pulmonary baseline resistance, airway hyper-reactivity, and airway collagen and smooth muscle expression in male C57Bl/6 mice. Responses were dependent on the level of calcium arsenate in the simulated dust. These changes were not associated with increased expression of TGF-β1, a marker of epithelial to mesenchymal transition. However, responses were correlated with decreases in the expression of club cell protein 16 (CC16). Dose-dependent decreases in CC16 expression and increases in collagen around airways was seen for animals exposed in utero only (GD), animals exposed postnatally only (PN) and animals continuously exposed throughout development (GDPN). These data suggest that arsenic inhalation during lung development can decrease CC16 expression leading to functional and structural alterations in the adult lung.
• Liu, Y., Liu, F., Liang, W., Zhu, L., Lantz, R. C., Zhu, J., & Chen, Y. (2020). Arsenic represses airway epithelial mucin expression by affecting retinoic acid signaling pathway. Toxicology and applied pharmacology, 394, 114959.
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  Arsenic is a ubiquitous environmental toxicant, found in high concentrations worldwide. Although abundant research has dealt with arsenic-induced cancers, studies on mechanisms of non-malignant lung diseases have not been complete. In addition, decades of research have mostly concentrated on high-dose arsenic exposure, which has very limited use in modeling the biological effects of today's low-dose exposures. Indeed, accumulated evidence has shown that low-dose arsenic exposure (i.e. ≤100 ppb) may also alter lung homeostasis by causing host susceptibility to viral infection. However, the underlying mechanism of this alteration is unknown. In this study, we found that low-dose sodium arsenite (As (III)) repressed major airway mucins-MUC5AC and MUC5B at both mRNA and protein levels. We further demonstrated that this repression was not caused by cellular toxicity or mediated by the reduction of a common mucin-inducing pathway-EGFR. Other established mucin activators- dsRNA, IL1β or IL17 were not able to override As (III)-induced mucin repression. Interestingly, the suppressing effect of As (III) appeared to be partially reversible, and supplementation of all trans retinoic acid (t-RA) doses dependently restored mucin gene expression. Further analyses indicated that As (III) treatment significantly reduced the protein level of retinoic acid receptors (RARα, γ and RXRα) as well as RARE promoter reporter activity. Therefore, our study fills in an important knowledge gap in the field of low-dose arsenic exposure. The interference of RA signaling, and mucin gene expression may be important pathogenic factors in low-dose arsenic induced lung toxicity.
• García-Rico, L., Meza-Figueroa, D., Beamer, P. I., Burgess, J. L., O'Rourke, M. K., Lantz, C. R., Furlong, M., Martinez-Cinco, M., Mondaca-Fernandez, I., Balderas-Cortes, J. J., & Meza-Montenegro, M. M. (2019). Serum matrix metalloproteinase-9 in children exposed to arsenic from playground dust at elementary schools in Hermosillo, Sonora, Mexico. Environmental geochemistry and health.
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  Arsenic exposure in adults has been associated with increased serum matrix metalloproteinase-9 (MMP-9), a biomarker which is associated with chronic respiratory disease, lung inflammation, cardiovascular disease and cancer. The objective of this study was to evaluate the association between serum MMP-9 levels in children, urinary arsenic, arsenic chronic daily intake (CDI) and arsenic exposure from playground dust. This cross-sectional study examined 127 children from five elementary schools, in Hermosillo, Sonora, Mexico. Arsenic was analyzed in the dust using a portable X-ray fluorescence (XRF) analyzer. Total urinary arsenic was determined by inductively coupled plasma/optical emission spectrometry. Serum was analyzed for MMP-9 using ELISA. Arsenic levels in playground dust averaged 16.9 ± 4.6 mg/kg. Urinary arsenic averaged 34.9 ± 17.1 µg/L. Arsenic concentration in playground dust was positively associated with serum MMP-9 levels in crude analyses and after adjustment (P 
• Michel-Ramirez, G., Recio-Vega, R., Lantz, R. C., Gandolfi, A. J., Olivas-Calderon, E., Chau, B. T., & Amistadi, M. K. (2019). Assessment of YAP gene polymorphisms and arsenic interaction in Mexican women with breast cancer. Journal of applied toxicology : JAT.
• Witten, M. L., Chau, B., Sáez, E., Boitano, S., & Clark Lantz, R. (2019). Early life inhalation exposure to mine tailings dust affects lung development. Toxicology and applied pharmacology, 365, 124-132.
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  Exposure to mine tailings dust from active and abandoned mining operations may be a very significant health hazard, especially to sensitive populations living in arid and semi-arid climates like the desert southwest of the US. It is anticipated that early life exposures during sensitive times of development can lead to adult disease. However, very few studies have investigated the effects of inhalation exposure to real world dusts during lung development. Using a mouse model, we have examined the effect(s) of inhalation of real world mine tailing dusts under three separate conditions: (1) Exposure only during in utero development (exposure of the pregnant moms) (2) exposure only after birth and (3) exposures that occurred continuously during in utero development, through gestation and birth until the mice reached adulthood (28 days old). We found that the most significant changes in lung structure and function were observed in male mice when exposure occurred continuously throughout development. These changes included increased airway hyper-reactivity, increased expression of epithelial to mesenchymal (EMT) transition protein markers and increased expression of cytokines related to eosinophils. The data also indicate that in utero exposures through maternal inhalation can prime the lung of male mice for more severe responses to subsequent postnatal exposures. This may be due to epigenetic alterations in gene regulation, immune response, molecular signaling, and growth factors involved in lung development that may make the neonatal lung more susceptible to continued dust exposure.
• Maldonado Escalante, J. F., Meza Figueroa, D., Dévora Figueroa, A. G., García Rico, L., Burgess, J. L., Lantz, R. C., Yañez Estrada, L., Martínez Cinco, M. A., Balderas Cortés, J. d., Mondaca Fernández, I., & Meza Montenegro, M. M. (2018). An integrated health risk assessment of indigenous children exposed to arsenic in Sonora, Mexico. Human and Ecological Risk Assessment: An International Journal, 25(3), 706-721. doi:10.1080/10807039.2018.1449098
• Thomas, A. N., Root, R. A., Lantz, R. C., Sáez, A. E., & Chorover, J. (2018). Oxidative weathering decreases bioaccessibility of toxic metal(loid)s in PM emissions from sulfide mine tailings. GeoHealth, 2(4), 118-138.
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  Environmental contamination from legacy mine-waste deposits is a persistent problem due to the long history of hard-rock mining. Sulfide ore deposits can contain elevated levels of toxic metal(loid)s that, when mobilized by weathering upon O and HO infusion, can result in groundwater contamination. Dry-climate and lack of vegetative cover result in near-surface pedogenic processes that produce fine-particulate secondary minerals that can be translocated as geo-dusts leading to ingestion or inhalation exposure in nearby communities. In this study, bioassays were combined with synchrotron-based x-ray spectroscopy and diffraction to determine the potential risk for toxic element release from dust (PM) samples into biofluid simulants. PM were isolated from across the oxidative reaction front in the top meter of tailings subjected to 50 years of weathering under semi-arid climate, and introduced to synthetic gastric- and alveolar-fluids. Aqueous concentrations were measured as a function of reaction time to determine release kinetics. X-ray diffraction and absorption spectroscopy analyses were performed to assess associated changes in mineralogy and elemental speciation. bioaccessibility of arsenic and lead was highest in less-weathered tailings samples (80-110 cm) and lowest in samples from the sub-oxic transition zone (40-52 cm). Conversely, zinc release to biofluids was greatest in the highly-weathered near-surface tailings. Results indicate that bioaccessibility of As and Pb was controlled by (i) the solubility of Fe-bearing solids, (ii) the prevalence of soluble SO, and (iii) the presence of poorly-crystalline Fe(III) oxide sorbents, whereas Zn bioaccessibility was controlled by the pH-dependent solubility of the stable solid phase.
• Yellowhair, M., Romanotto, M. R., Stearns, D. M., & Clark Lantz, R. (2018). Uranyl acetate induced DNA single strand breaks and AP sites in Chinese hamster ovary cells. Toxicology and applied pharmacology, 349, 29-38.
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  The aim of this study is to characterize the genotoxicity of depleted uranium (DU) in Chinese Hamster Ovary cells (CHO) with mutations in various DNA repair pathways. CHO cells were exposed to 0-300 μM of soluble DU as uranyl acetate (UA) for 0-48 h. Intracellular UA concentrations were measured via inductively coupled mass spectrometry (ICP-MS) and visualized by transmission electron microscopy (TEM). Cytotoxicity was assessed in vitro by clonogenic survival assay. DNA damage response was assessed via Fast Micromethod® to determine UA-induced DNA single strand breaks. Results indicate that UA is entering the CHO cells, with the highest concentration localizing in the nucleus. Clonogenic assays show that UA is cytotoxic in each cell line with the greatest cytotoxicity in the base excision repair deficient EM9 cells and the nuclear excision repair deficient UV5 cells compared to the non-homologous end joining deficient V3.3 cells and the parental AA8 cells after 48 h. This indicates that UA is producing single strand breaks and forming UA-DNA adducts rather than double strand breaks in CHO cells. Fast Micromethod® results indicate an increased amount of single strand breaks in the EM9 cells after 48 h UA exposure compared to the V3.3 and AA8 cells. These results indicate that DU induces DNA damage via strand breaks and uranium-DNA adducts in treated cells. These results suggest that: (1) DU is genotoxic in CHO cells, and (2) DU is inducing single strand breaks rather than double strand breaks in vitro.
• Gonzalez-Cortes, T., Recio-Vega, R., Lantz, R. C., & Chau, B. T. (2017). DNA methylation of extracellular matrix remodeling genes in children exposed to arsenic. Toxicology and applied pharmacology, 329, 140-147.
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  Several novel mechanistic findings regarding to arsenic's pathogenesis has been reported and some of them suggest that the etiology of some arsenic induced diseases are due in part to heritable changes to the genome via epigenetic processes such as DNA methylation, histone maintenance, and mRNA expression. Recently, we reported that arsenic exposure during in utero and early life was associated with impairment in the lung function and abnormal receptor for advanced glycation endproducts (RAGE), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) sputum levels. Based on our results and the reported arsenic impacts on DNA methylation, we designed this study in our cohort of children exposed in utero and early childhood to arsenic with the aim to associate DNA methylation of MMP9, TIMP1 and RAGE genes with its protein sputum levels and with urinary and toenail arsenic levels. The results disclosed hypermethylation in MMP9 promotor region in the most exposed children; and an increase in the RAGE sputum levels among children with the mid methylation level; there were also positive associations between MMP9 DNA methylation with arsenic toenail concentrations; RAGE DNA methylation with iAs, and %DMA; and finally between TIMP1 DNA methylation with the first arsenic methylation. A negative correlation between MMP9 sputum levels with its DNA methylation was registered. In conclusion, arsenic levels were positive associated with the DNA methylation of extracellular matrix remodeling genes;, which in turn could modifies the biological process in which they are involved causing or predisposing to lung diseases.
• Hays, A. M., Lantz, R. C., & Witten, M. L. (2017). Correlation between in vivo and in vitro pulmonary responses to jet propulsion fuel-8 using precision-cut lung slices and a dynamic organ culture system. Toxicologic pathology, 31(2), 200-7.
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  In tissue slice models, interactions between the heterogeneous cell types comprising the lung parenchyma are maintained thus providing a controlled system for the study of pulmonary toxicology in vitro. However, validation of the model in vitro system must be affirmed. Previous reports, in in vivo systems, have demonstrated that Clara cells and alveolar type II cells are the targets following inhalation of JP-8 jet fuel. We have utilized the lung slice model to determine if cellular targets are similar following in vitro exposure to JP-8. Agar-filled adult rat lung explants were cored and precision cut, using the Brende/Vitron tissue slicer. Slices were cultured on titanium screens located as half-cylinders in cylindrical Teflon cradles that were loaded into standard scintillation vials and incubated at 37 degrees C. Slices were exposed to JP-8 jet fuel (0.5 mg/ml, 1.0 mg/ml, and 1.5 mg/ml in medium) for up to 24 hours. We determined ATP content using a luciferin-luciferase bioluminescent assay. No significant difference was found between the JP-8 jet fuel doses or time points, when compared to controls. Results were correlated with structural alterations following aerosol inhalation of JP-8. As a general observation, ultrastructural evaluation of alveolar type cells revealed an apparent increase in the number and size of surfactant secreting lamellar bodies that was JP-8 jet fuel-dose dependent. These results are similar to those observed following aerosol inhalation exposure. Thus, the lung tissue slice model appears to mimic in vivo effects of JP-8 and therefore is a useful model system for studying the mechanisms of lunginjury following JP-8 exposure.
• Michel-Ramirez, G., Recio-Vega, R., Ocampo-Gomez, G., Palacios-Sanchez, E., Delgado-Macias, M., Delgado-Gaona, M., Lantz, R. C., Gandolfi, J., & Gonzalez-Cortes, T. (2017). Association between YAP expression in neoplastic and non-neoplastic breast tissue with arsenic urinary levels. Journal of applied toxicology : JAT, 37(10), 1195-1202.
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  The Hippo pathway regulates cell proliferation and apoptosis and it has been noted that loss of critical components of this pathway can lead to uncontrolled cell growth. Yes-associated protein (YAP) is an important component of this Hippo pathway because YAP is the nuclear effector of the Hippo tumor suppressor pathway and it is crucial for the response to oxidative stress induced by cellular process and by different xenobiotics, including arsenic. It has been proposed that YAP dysregulation can contribute to a malignant cellular phenotype acting as both a tumor suppressor and an oncogene. The aim of the study was to assess and compare the expression of YAP in neoplastic and non-neoplastic breast tissue of women chronically exposed to arsenic through drinking water. YAP expression was assessed by immunohistochemistry in 120 breast biopsies from women with breast cancer and from women with other non-neoplastic breast pathologies. Arsenic concentration was quantified in urine. The results disclosed a significant lower percentage of cytoplasm YAP expression in cases and that YAP high-intensity staining in the cytoplasm but not in the nucleus decreases the risk for breast cancer. In conclusion, our overall data suggest that YAP may act as a tumor suppressor protein because their reduced expression in cases, which can induce an environment favorable for inhibition of apoptosis and promoting cellular proliferation by increasing genetic instability of cells, which might contribute to the pathogenesis of cancer. Copyright © 2017 John Wiley & Sons, Ltd.
• Smeester, L., Bommarito, P. A., Martin, E. M., Recio-Vega, R., Gonzalez-Cortes, T., Olivas-Calderon, E., Lantz, R. C., & Fry, R. C. (2017). Chronic early childhood exposure to arsenic is associated with a TNF-mediated proteomic signaling response. Environmental toxicology and pharmacology, 52, 183-187.
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  Exposure to inorganic arsenic (iAs) in drinking water is a global public health concern and is associated with a range of health outcomes, including immune dysfunction. Children are a particularly sensitive population to the effects of inorganic arsenic, yet the biological mechanisms underlying adverse health outcomes are understudied. Here we used a proteomic approach to examine the effects of iAs exposure on circulating serum protein levels in a cross-sectional children's cohort in Mexico. To identify iAs-associated proteins, levels of total urinary arsenic (U-tAs) and its metabolites were determined and serum proteins assessed for differences in expression. The results indicate an enrichment of Tumor Necrosis Factor-(TNF)-regulated immune and inflammatory response proteins that displayed decreased expression levels in relation to increasing U-tAs. Notably, when analyzed in the context of the proportions of urinary arsenic metabolites in children, the most robust response was observed in relation to the monomethylated arsenicals. This study is among the first serum proteomics assessment in children exposed to iAs.
• Beamer, P. I., Klimecki, W. T., Loh, M., Van Horne, Y. O., Sugeng, A. J., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. D. (2016). Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. International journal of environmental research and public health, 13(5).
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  Arsenic exposure has been associated with decreased club cell secretory protein (CC16) levels in adults. Further, both arsenic exposure and decreased levels of CC16 in childhood have been associated with decreased adult lung function. Our objective was to determine if urinary CC16 levels in children are associated with arsenic concentrations in environmental media collected from their homes. Yard soil, house dust, and tap water were taken from 34 homes. Urine and toenail samples were collected from 68 children. All concentrations were natural log-transformed prior to data analysis. There were associations between urinary CC16 and arsenic concentration in soil (b = -0.43, p = 0.001, R² = 0.08), water (b = -0.22, p = 0.07, R² = 0.03), house dust (b = -0.37, p = 0.07, R² = 0.04), and dust loading (b = -0.21, p = 0.04, R² = 0.04). In multiple analyses, only the concentration of arsenic in soil was associated with urinary CC16 levels (b = -0.42, p = 0.02, R² = 0.14 (full model)) after accounting for other factors. The association between urinary CC16 and soil arsenic may suggest that localized arsenic exposure in the lungs could damage the airway epithelium and predispose children for diminished lung function. Future work to assess this possible mechanism should examine potential associations between airborne arsenic exposures, CC16 levels, lung function, and other possible confounders in children in arsenic-impacted communities.
• Beamer, P. I., Klimecki, W. T., Loh, M., Van Horne, Y. O., Sugeng, A. J., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. D. (2016). Response to García-Nieto et al. Comments on Beamer et al. Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. Int. J. Environ. Res. Public Health 2016, 13, 521. International journal of environmental research and public health, 13(10).
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  We would like to thank the editors for providing us with the opportunity to respond to the points raised by Dr. García Nieto.[...].
• Beamer, P. I., Klimecki, W. T., Loh, M., Van, H., Sugeng, A. J., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. D. (2016). Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH, 13(5).
• Beamer, P. I., Klimecki, W. T., Loh, M., Van, H., Sugeng, A. J., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. D. (2016). Response to Garcia-Nieto et al. Comments on Beamer et al. Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. Int. J. Environ. Res. Public Health 2016, 13, 521. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH, 13(10).
• Beamer, P., Klimecki, W., Loh, M., Van Horne, Y. O., Sugeng, A., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., & Martinez, F. (2016). Association of Children’s Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. International Journal of Environmental Research and Public Health, 13(5), E521. doi:10.3390/ijerph13050521
• Recio-Vega, R., González-Cortes, T., Olivas-Calderón, E., Clark Lantz, R., Jay Gandolfi, A., & Michel-Ramirez, G. (2016). Association between polymorphisms in arsenic metabolism genes and urinary arsenic methylation profiles in girls and boys chronically exposed to arsenic. Environmental and molecular mutagenesis, 57(7), 516-25.
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  Disease manifestations or susceptibilities often differ among individuals exposed to the same concentrations of arsenic (As). These differences have been associated with several factors including As metabolism, sex, age, genetic variants, nutritional status, smoking, and others. This study evaluated the associations between four As metabolism-related gene polymorphisms/null genotypes with urinary As methylation profiles in girls and boys chronically exposed to As. In a total of 332 children aged 6-12 years, the frequency of AS3MT, GSTO1, GSTT1, and GSTM1 polymorphisms/null genotypes and As urinary metabolites were measured. The results revealed that total As and monomethyl metabolites of As (MMA) levels were higher in boys than in girls. No differences in the frequency of the evaluated polymorphisms were found between girls and boys. In AS3MT-Met287Thr carriers, %MMA levels were higher and second methylation levels (defined as dimethylarsinic acid divided by MMA) were lower. In children with the GSTM1 null genotype, second methylation levels were higher. In boys, a positive association between the AS3MT-Met287Thr polymorphism with %MMA and between the GSTO1-Glu155del and As(v) was found; whereas, a negative relationship was identified between AS3MT-Met287Thr and second methylation profiles. In girls, a positive association was found between the GSTO1-Ala140Asp polymorphism with second methylation levels. In conclusion, our data indicate that gender, high As exposure levels, and polymorphisms in the evaluated genes negatively influenced As metabolism. Environ. Mol. Mutagen. 57:516-525, 2016. © 2016 Wiley Periodicals, Inc.
• de la Vega, M. R., Dodson, M., Gross, C., Manzour, H., Lantz, R. C., Chapman, E., Wang, T., Black, S. M., Garcia, J. G., & Zhang, D. D. (2016). Role of Nrf2 and Autophagy in Acute Lung Injury. Current pharmacology reports, 2(2), 91-101.
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  Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function. Since the airways and lung tissues are constantly exposed to gaseous oxygen and airborne toxicants, the bronchial and alveolar epithelial cells are under higher oxidative stress than other tissues. Cellular protection against oxidative stress and xenobiotics is mainly conferred by Nrf2, a transcription factor that promotes the expression of genes that regulate oxidative stress, xenobiotic metabolism and excretion, inflammation, apoptosis, autophagy, and cellular bioenergetics. Numerous studies have demonstrated the importance of Nrf2 activation in the protection against ALI/ARDS, as pharmacological activation of Nrf2 prevents the occurrence or mitigates the severity of ALI/ARDS. Another promising new therapeutic strategy in the prevention and treatment of ALI/ARDS is the activation of autophagy, a bulk protein and organelle degradation pathway. In this review, we will discuss the strategy of concerted activation of Nrf2 and autophagy as a preventive and therapeutic intervention to ameliorate ALI/ARDS.
• Burgess, J. L., Kurzius-Spencer, M., Poplin, G. S., Littau, S. R., Kopplin, M. J., Stürup, S., Boitano, S., & Clark Lantz, R. (2014). Environmental arsenic exposure, selenium and sputum alpha-1 antitrypsin. Journal of exposure science & environmental epidemiology, 24(2), 150-5.
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  Exposure to arsenic in drinking water is associated with increased respiratory disease. Alpha-1 antitrypsin (AAT) protects the lung against tissue destruction. The objective of this study was to determine whether arsenic exposure is associated with changes in airway AAT concentration and whether this relationship is modified by selenium. A total of 55 subjects were evaluated in Ajo and Tucson, Arizona. Tap water and first morning void urine were analyzed for arsenic species, induced sputum for AAT and toenails for selenium and arsenic. Household tap-water arsenic, toenail arsenic and urinary inorganic arsenic and metabolites were significantly higher in Ajo (20.6±3.5 μg/l, 0.54±0.77 μg/g and 27.7±21.2 μg/l, respectively) than in Tucson (3.9±2.5 μg/l, 0.16±0.20 μg/g and 13.0±13.8 μg/l, respectively). In multivariable models, urinary monomethylarsonic acid (MMA) was negatively, and toenail selenium positively associated with sputum AAT (P=0.004 and P=0.002, respectively). In analyses stratified by town, these relationships remained significant only in Ajo, with the higher arsenic exposure. Reduction in AAT may be a means by which arsenic induces respiratory disease, and selenium may protect against this adverse effect.
• Burgess, J. L., Meza, M. M., Josyula, A. B., Poplin, G. S., Kopplin, M. J., McClellen, H. E., Stürup, S., & Lantz, R. C. (2015). Environmental Arsenic Exposure and Urinary 8-OHdG in Arizona and Sonora. Clinical toxicology (Philadelphia, Pa.), 45(5), 490-8.
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  Although at high levels arsenic exposure is associated with increased cancer incidence, information on the health effects of lower exposure levels is limited. The objective of this study was to determine whether arsenic at concentrations below 40 microg/L in drinking water is associated with increased urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of DNA oxidative damage and repair. Urine samples were collected from 73 nonsmoking adults residing in two communities in Arizona (mean tap water arsenic (microg/L) 4.0 +/- 2.3 and 20.3 +/- 3.7), and 51 subjects in four communities in Sonora, Mexico (mean tap water arsenic (microg/L) ranging from 4.8 +/- 0.1 to 33.3 +/- 0.6). Although urinary arsenic concentration increased with higher exposure in tap water, urinary 8-OHdG concentration did not differ by community within Arizona or Sonora, and was not associated with urinary arsenic concentration. At the exposure levels evaluated in this study, drinking water arsenic was not associated with increased DNA oxidation as measured by urinary 8-OHdG.
• Olivas-Calderón, E., Recio-Vega, R., Gandolfi, A. J., Lantz, R. C., González-Cortes, T., Gonzalez-De Alba, C., Froines, J. R., & Espinosa-Fematt, J. A. (2015). Lung inflammation biomarkers and lung function in children chronically exposed to arsenic. Toxicology and applied pharmacology, 287(2), 161-7.
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  Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases.
• Recio-Vega, R., Gonzalez-Cortes, T., Olivas-Calderon, E., Lantz, R. C., Gandolfi, A. J., & Alba, C. G. (2015). In utero and early childhood exposure to arsenic decreases lung function in children. Journal of applied toxicology : JAT, 35(4), 358-66.
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  The lung is a target organ for adverse health outcomes following exposure to As. Several studies have reported a high prevalence of respiratory symptoms and diseases in subjects highly exposed to As through drinking water; however, most studies to date has been performed in exposed adults, with little information on respiratory effects in children. The objective of the study was to evaluate the association between urinary levels of As and its metabolites with lung function in children exposed in utero and in early childhood to high As levels through drinking water. A total of 358 healthy children were included in our study. Individual exposure was assessed based on urinary concentration of inorganic As. Lung function was assessed by spirometry. Participants were exposed since pregnancy until early childhood to an average water As concentration of 152.13 µg l(-1) . The mean urinary As level registered in the studied subjects was 141.2 µg l(-1) and only 16.7% had a urinary concentration below the national concern level. Forced vital capacity was significantly decreased in the studied population and it was negatively associated with the percentage of inorganic As. More than 57% of the subjects had a restrictive spirometric pattern. The urinary As level was higher in those children with restrictive lung patterns when compared with the levels registered in subjects with normal spirometric patterns. Exposure to As through drinking water during in utero and early life was associated with a decrease in forced vital capacity and with a restrictive spirometric pattern in the children evaluated.
• Stanton, B. A., Caldwell, K., Congdon, C. B., Disney, J., Donahue, M., Ferguson, E., Flemings, E., Golden, M., Guerinot, M. L., Highman, J., James, K., Kim, C., Lantz, R. C., Marvinney, R. G., Mayer, G., Miller, D., Navas-Acien, A., Nordstrom, D. K., Postema, S., , Rardin, L., et al. (2015). MDI Biological Laboratory Arsenic Summit: Approaches to Limiting Human Exposure to Arsenic. Current environmental health reports, 2(3), 329-37.
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  This report is the outcome of the meeting "Environmental and Human Health Consequences of Arsenic" held at the MDI Biological Laboratory in Salisbury Cove, Maine, August 13-15, 2014. Human exposure to arsenic represents a significant health problem worldwide that requires immediate attention according to the World Health Organization (WHO). One billion people are exposed to arsenic in food, and more than 200 million people ingest arsenic via drinking water at concentrations greater than international standards. Although the US Environmental Protection Agency (EPA) has set a limit of 10 μg/L in public water supplies and the WHO has recommended an upper limit of 10 μg/L, recent studies indicate that these limits are not protective enough. In addition, there are currently few standards for arsenic in food. Those who participated in the Summit support citizens, scientists, policymakers, industry, and educators at the local, state, national, and international levels to (1) establish science-based evidence for setting standards at the local, state, national, and global levels for arsenic in water and food; (2) work with government agencies to set regulations for arsenic in water and food, to establish and strengthen non-regulatory programs, and to strengthen collaboration among government agencies, NGOs, academia, the private sector, industry, and others; (3) develop novel and cost-effective technologies for identification and reduction of exposure to arsenic in water; (4) develop novel and cost-effective approaches to reduce arsenic exposure in juice, rice, and other relevant foods; and (5) develop an Arsenic Education Plan to guide the development of science curricula as well as community outreach and education programs that serve to inform students and consumers about arsenic exposure and engage them in well water testing and development of remediation strategies.
• Calderon, E. H., Calderon, E. H., Fematt, J. A., Fematt, J. A., Vega, R. R., Gomez, G. O., Gonzalez, T. C., Lantz, R. C., Gandolfi, A. J., Vega, R. R., Lantz, R. C., Gonzalez, T. C., Gomez, G. O., & Gandolfi, A. J. (2014). Lung function and pulmonary biomarkers in children chronically exposed to arsenic in drinking water. As 2014 - Proceedings of the 5th International Congress on Arsenic in the Environment.
• Sherwood, C. L., Lantz, R. C., & Boitano, S. (2013). Chronic arsenic exposure in nanomolar concentrations compromises wound response and intercellular signaling in airway epithelial cells. Toxicological sciences : an official journal of the Society of Toxicology, 132(1), 222-34.
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  Paracrine ATP signaling in the lung epithelium participates in a variety of innate immune functions, including mucociliary clearance, bactericide production, and as an initiating signal in wound repair. We evaluated the effects of chronic low-dose arsenic relevant to U.S. drinking water standards (i.e., 10 ppb [130nM]) on airway epithelial cells. Immortalized human bronchial epithelial cells (16HBE14o-) were exposed to 0, 130, or 330nM arsenic (as Na-arsenite) for 4-5 weeks and examined for wound repair efficiency and ATP-mediated Ca(2+) signaling. We found that chronic arsenic exposure at these low doses slows wound repair and reduces ATP-mediated Ca(2+) signaling. We further show that arsenic compromises ATP-mediated Ca(2+) signaling by altering both Ca(2+) release from intracellular stores (via metabotropic P2Y receptors) and Ca(2+) influx mechanisms (via ionotropic P2X receptors). To better model the effects of arsenic on ATP-mediated Ca(2+) signaling under conditions of natural exposure, we cultured tracheal epithelial cells obtained from mice exposed to control or 50 ppb Na-arsenite supplemented drinking water for 4 weeks. Tracheal epithelial cells from arsenic-exposed mice displayed reduced ATP-mediated Ca(2+) signaling dynamics similar to our in vitro chronic exposure. Our findings demonstrate that chronic arsenic exposure at levels that are commonly found in drinking water (i.e., 10-50 ppb) alters cellular mechanisms critical to airway innate immunity.
• Sherwood, C. L., Liguori, A. E., Olsen, C. E., Lantz, R. C., Burgess, J. L., & Boitano, S. (2013). Arsenic compromises conducting airway epithelial barrier properties in primary mouse and immortalized human cell cultures. PloS one, 8(12), e82970.
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  Arsenic is a lung toxicant that can lead to respiratory illness through inhalation and ingestion, although the most common exposure is through contaminated drinking water. Lung effects reported from arsenic exposure include lung cancer and obstructive lung disease, as well as reductions in lung function and immune response. As part of their role in innate immune function, airway epithelial cells provide a barrier that protects underlying tissue from inhaled particulates, pathogens, and toxicants frequently found in inspired air. We evaluated the effects of a five-day exposure to environmentally relevant levels of arsenic {
• Tao, S., Zheng, Y., Lau, A., Jaramillo, M. C., Chau, B. T., Lantz, R. C., Wong, P. K., Wondrak, G. T., & Zhang, D. D. (2013). Tanshinone I activates the Nrf2-dependent antioxidant response and protects against As(III)-induced lung inflammation in vitro and in vivo. Antioxidants & redox signaling, 19(14), 1647-61.
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  The NF-E2 p45-related factor 2 (Nrf2) signaling pathway regulates the cellular antioxidant response and activation of Nrf2 has recently been shown to limit tissue damage from exposure to environmental toxicants, including As(III). In an attempt to identify improved molecular agents for systemic protection against environmental insults, we have focused on the identification of novel medicinal plant-derived Nrf2 activators.
• Boitano, S. A., Sherwood, C. L., Burgess, J. L., & Lantz, R. C. (2012). Low-level Arsenic Alters Lung Epithelial Wound Repair. Proceedings of the American Thoracic Society.
• Zheng, Y., Tao, S., Lian, F., Chau, B. T., Chen, J., Sun, G., Fang, D., Lantz, R. C., & Zhang, D. D. (2012). Sulforaphane prevents pulmonary damage in response to inhaled arsenic by activating the Nrf2-defense response. Toxicology and applied pharmacology, 265(3), 292-9.
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  Exposure to arsenic is associated with an increased risk of lung disease. Novel strategies are needed to reduce the adverse health effects associated with arsenic exposure in the lung. Nrf2, a transcription factor that mediates an adaptive cellular defense response, is effective in detoxifying environmental insults and prevents a broad spectrum of diseases induced by environmental exposure to harmful substances. In this report, we tested whether Nrf2 activation protects mice from arsenic-induced toxicity. We used an in vivo arsenic inhalation model that is highly relevant to low environmental human exposure to arsenic-containing dusts. Two-week exposure to arsenic-containing dust resulted in pathological alterations, oxidative DNA damage, and mild apoptotic cell death in the lung; all of which were blocked by sulforaphane (SF) in an Nrf2-dependent manner. Mechanistically, SF-mediated activation of Nrf2 alleviated inflammatory responses by modulating cytokine production. This study provides strong evidence that dietary intervention targeting Nrf2 activation is a feasible approach to reduce adverse health effects associated with arsenic exposure.
• Cara L. Sherwood, ., Lantz, R. C., Burgess, J. L., & Boitano, S. A. (2011). Arsenic alters ATP-dependent Ca 2+ signaling in human airway epithelial cell wound response. Toxicological Sciences, 121(1), 191-206.
• Sherwood, C. L., Lantz, R. C., Burgess, J. L., & Boitano, S. (2011). Arsenic alters ATP-dependent Ca²+ signaling in human airway epithelial cell wound response. Toxicological sciences : an official journal of the Society of Toxicology, 121(1), 191-206.
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  Arsenic is a natural metalloid toxicant that is associated with occupational inhalation injury and contaminates drinking water worldwide. Both inhalation of arsenic and consumption of arsenic-tainted water are correlated with malignant and nonmalignant lung diseases. Despite strong links between arsenic and respiratory illness, underlying cell responses to arsenic remain unclear. We hypothesized that arsenic may elicit some of its detrimental effects on the airway through limitation of innate immune function and, specifically, through alteration of paracrine ATP (purinergic) Ca²+ signaling in the airway epithelium. We examined the effects of acute (24 h) exposure with environmentally relevant levels of arsenic (i.e., < 4 μM as Na-arsenite) on wound-induced Ca²+ signaling pathways in human bronchial epithelial cell line (16HBE14o-). We found that arsenic reduces purinergic Ca²+ signaling in a dose-dependent manner and results in a reshaping of the Ca²+ signaling response to localized wounds. We next examined arsenic effects on two purinergic receptor types: the metabotropic P2Y and ionotropic P2X receptors. Arsenic inhibited both P2Y- and P2X-mediated Ca²+ signaling responses to ATP. Both inhaled and ingested arsenic can rapidly reach the airway epithelium where purinergic signaling is essential in innate immune functions (e.g., ciliary beat, salt and water transport, bactericide production, and wound repair). Arsenic-induced compromise of such airway defense mechanisms may be an underlying contributor to chronic lung disease.
• States, J. C., Barchowsky, A., Cartwright, I. L., Reichard, J. F., Futscher, B. W., & Lantz, R. C. (2011). Arsenic toxicology: translating between experimental models and human pathology. Environmental health perspectives, 119(10), 1356-63.
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  Chronic arsenic exposure is a worldwide health problem. How arsenic exposure promotes a variety of diseases is poorly understood, and specific relationships between experimental and human exposures are not established. We propose phenotypic anchoring as a means to unify experimental observations and disease outcomes.
• Wong, S. S., Sun, N. N., Fastje, C. D., Witten, M. L., Lantz, R. C., Lu, B., Sherrill, D. L., Gerard, C. J., Burgess, J. L., & , H. H. (2011). Role of neprilysin in airway inflammation induced by diesel exhaust emissions. Research report (Health Effects Institute), 3-40.
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  In this study, we examined the role of neprilysin (NEP), a key membrane-bound endopeptidase, in the inflammatory response induced by diesel exhaust emissions (DEE) in the airways through a number of approaches: in vitro, animal, and controlled human exposure. Our specific aims were (1) to examine the role of NEP in inflammatory injury induced by diesel exhaust particles (DEP) using Nep-intact (wild-type) and Nep-null mice; (2) to examine which components of DEP are associated with NEP downregulation in vitro; (3) to determine the molecular impact of DEP exposure and decreased NEP expression on airway epithelial cells' gene expression in vitro, using a combination of RNA interference (RNAi) and microarray approaches; and (4) to evaluate the effects on NEP activity of human exposure to DEE. We report four main results: First, we found that exposure of normal mice to DEP consisting of standard reference material (SRM) 2975 via intratracheal installation can downregulate NEP expression in a concentration-dependent manner. The changes were accompanied by increases in the number of macrophages and epithelial cells, as well as proinflammatory cytokines, examined in bronchoalveolar lavage (BAL) fluid and cells. Nep-null mice displayed increased and/or additional inflammatory responses when compared with wild-type mice, especially in response to exposure to the higher dose of DEP that we used. These in vivo findings suggest that loss of NEP in mice could cause increased susceptibility to injury or exacerbate inflammatory responses after DEP exposure via release of specific cytokines from the lungs. Second, we found evidence, using in vitro studies, that downregulation of NEP by DEP in cultured human epithelial BEAS-2B cells was mostly attributable to DEP-adsorbed organic compounds, whereas the carbonaceous core and transition metal components of DEP had little or no effect on NEP messenger RNA (mRNA) expression. This NEP downregulation was not a specific response to DEP or its contents because the change also occurred after exposure to urban dust (SRM 1649a), which differs in physical and chemical composition from DEP. Third, we also collected the transcriptome profiles of the concentration-effects of SRM 2975 in cultured BEAS-2B cells through a 2 X 3 factorial design. DEP exposure upregulated 151 genes and downregulated 59 genes. Cells with decreased NEP expression (accomplished by transfecting an NEP-specific small interfering RNA [siRNA]) substantially altered the expression of genes (upregulating 17 and downregulating 14) associated with DNA/protein binding, calcium channel activities, and the cascade of intracellular signaling by cytokines. Data generated from the combined RNAi and microarray approaches revealed that there is a complex molecular cascade mediated by NEP in different subcellular compartments, possibly influencing the inflammatory response. Fourth, in a controlled human exposure study, we observed significant increases in soluble NEP in sputum after acute exposure to DEE, with an average net increase of 31%. We speculate that the change in NEP activity in sputum, if confirmed in larger epidemiologic investigations at ambient exposure levels to DEE, may provide a useful endpoint and promote insight into the mechanism of DEE-induced airway alterations.
• dos Santos, M. D., Chen, G., Almeida, M. C., Soares, D. M., de Souza, G. E., Lopes, N. P., & Lantz, R. C. (2010). Effects of caffeoylquinic acid derivatives and C-flavonoid from Lychnophora ericoides on in vitro inflammatory mediator production. Natural product communications, 5(5), 733-40.
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  In this study we aimed at evaluating the effect of the major polar constituents of the medicinal plant Lychnophora ericoides on the production of inflammatory mediators produced by LPS-stimulated U-937 cells. The 6,8-di-C-beta-glucosylapigenin (vicenin-2) presented no effect on tumor necrosis factor (TNF)-alpha production, but inhibited, in a dose-dependent manner, the production of prostaglandin (PG) E2 without altering the expression of cyclooxygenase (COX)-2 protein. 3,5-Dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid, at lower concentrations, had small but significant effects on reducing PGE2 levels; at higher doses these compounds stimulated PGE2 and also TNF-alpha production by the cells. All the caffeoylquinic acid derivatives, in a dose-dependent fashion, were able to inhibit monocyte chemoattractant protein-3 synthesis/release, with 4,5-DCQ being the most potent at the highest tested concentration. These results add important information on the effects of plant natural polyphenols, namely vicenin-2 and caffeoylquinic acid derivatives, on the production of inflammatory mediators by cultured cells.
• Lantz, R. C., Chau, B., Sarihan, P., Witten, M. L., Pivniouk, V. I., & Chen, G. J. (2009). In utero and postnatal exposure to arsenic alters pulmonary structure and function. Toxicology and applied pharmacology, 235(1), 105-13.
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  In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airway reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 microm in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.
• Petrick, J. S., Blachere, F. M., Selmin, O., & Lantz, R. C. (2009). Inorganic arsenic as a developmental toxicant: In utero exposure and alterations in the developing rat lungs. MOLECULAR NUTRITION & FOOD RESEARCH, 53(5), 583-591.
• Petrick, J. S., Blachere, F. M., Selmin, O., & Lantz, R. C. (2009). Inorganic arsenic as a developmental toxicant: in utero exposure and alterations in the developing rat lungs. Molecular nutrition & food research, 53(5), 583-91.
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  In the present study, we characterize the toxic effects of in utero arsenic exposure on the developing lung. We hypothesize that in utero exposure to inorganic arsenic through maternal drinking water causes altered gene and protein expression in the developing lung, indicative of downstream molecular and functional changes. From conception to embryonic day 18, we exposed pregnant Sprague-Dawley rats to 500 ppb arsenic (as arsenite) via the drinking water. Subtracted cDNA libraries comparing control to arsenic exposed embryonic lungs were generated. In addition, a broad Western blot analysis was performed to identify altered protein expression. A total of 59 genes and 34 proteins were identified as being altered. Pathway mapping and analysis showed that cell motility was the process most affected. The most likely affected pathway was alteration in integrin signaling through the beta-catenin pathway, altering c-myc. The present study shows that arsenic induces alterations in the developing lung. These data may be useful in the elucidation of molecular targets and biomarkers of arsenic exposure during lung development and may aid in understanding the etiology of arsenic induced adult respiratory disease and lung cancers.
• Sherwood, C. L., Olsen, C. E., Liguori, A. E., Lantz, R. C., Burgess, J. L., & Boitano, S. (2009). Arsenic alters P2 receptor-dependent Ca2+ signaling in human airway epithelial cells. The FASEB Journal, 23.
• Sherwood, C. L., Olsen, C. E., Liguori, A. E., Lantz, R. C., Burgess, J. L., & Boitano, S. (2009). Arsenic alters tight junction expression, distribution and function in human airway epithelial cells. The FASEB Journal, 23.
• Wong, S. S., Thomas, A., Barbaris, B., Lantz, R. C., & Witten, M. L. (2009). Pulmonary evaluation of permissible exposure limit of syntroleum S-8 synthetic jet fuel in mice. Toxicological sciences : an official journal of the Society of Toxicology, 109(2), 312-20.
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  No current studies have systematically examined pulmonary health effects associated with Syntroleum S-8 synthetic jet fuel (S-8). In order to gain an understanding about the threshold concentration in which lung injury is observed, C57BL/6 male mice were nose-only exposed to S-8 for 1 h/day for 7 days at average concentrations of 0 (control), 93, 352, and 616 mg/m(3). Evaluation of pulmonary function, airway epithelial barrier integrity, and pathohistology was performed 24 h after the final exposures. Significant decreases were detected in expiratory lung resistance and total lung compliance of the 352 mg/m(3) group, for which no clear concentration-dependent alterations could be determined. No significant changes in respiratory permeability were exhibited, indicating that there was no loss of epithelial barrier integrity following S-8 exposure. However, morphological examination and morphometric analysis of distal lung tissue, by using transmission electron microscopy, revealed cellular damage in alveolar type II epithelial cells, with significant increases in volume density of lamellar bodies/vacuoles at 352 and 616 S-8 mg/m(3). Moreover, terminal bronchiolar Clara injury, as evidenced by apical membrane blebs, was observed at relatively low concentrations, suggesting if this synthetic jet fuel is utilized, the current permissible exposure limit of 350 mg/m(3) for hydrocarbon fuels should cautiously be applied.
• Yellowhair, M., Lantz, R. C., Hossain, A., Henricksen, L. A., & Dixon, K. (2009). Abstract B41: Depleted uranium-induced oxidative stress in human bronchial epithelial cells. Cancer Epidemiology and Prevention Biomarkers, 18.
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  Cancer and mortality rates are on the rise in many populations exposed to high deposits of uranium or tailings. There is an increased concern over environmental exposure to abandoned uranium mine tailings as well as occupational exposures to depleted uranium via military action. Cellular oxidative stress has been implicated in the genotoxicity of many heavy metals. The aim of this study is to evaluate the toxicity of depleted uranium (DU) in its soluble and insoluble forms in human bronchial epithelial cells (16HBE14o−). 16HBE14o− cells were exposed to 30 ppb of soluble depleted uranium (uranyl acetate - UA) and insoluble depleted uranium (uranium trioxide - UO3, uranium dioxide - UO2, uranium oxide - U3O8) for 2 – 24 hr. Oxidative stress was assessed in vitro by 5(6)-carboxy-2′,7′ − dichlorofluorescein diacetate (H2DCFDA) staining and visualized by live cell fluorescent microscopy and flow cytometry. DNA damage response was assessed in vitro via Western immunoblotting to determine phosphorylation of histone H2AX and RPA levels. Results indicate that 16HBE14o− cells treated with UA and UO3 induced oxidative stress compared to untreated cells at 3 – 4 hr time points. 16HBE14o− cells treated with UA and UO3 induced phosphorylation of histone H2AX. These results are consistent with previous studies that indicate DU induces DNA damage via strand breaks and uranium-DNA adducts in treated cells. Interestingly, there was no increase in RPA phosphorylation levels of DU treated cells compared to untreated cells. These results suggest that: (1) cellular oxidative stress may be a pathway of particulate DU genotoxicity, and (2) induced DNA damage by DU may activate base excision repair in vitro. We are currently examining additional DNA repair targets to better understand the DNA repair pathway(s) stimulated by exposure to DU.
• Hays, A. M., Lantz, R. C., Rodgers, L. S., Sollome, J. J., Vaillancourt, R. R., Andrew, A. S., Hamilton, J. W., & Camenisch, T. D. (2008). Arsenic-induced decreases in the vascular matrix. Toxicologic pathology, 36(6), 805-17.
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  Chronic ingestion of arsenic is associated with increased incidence of respiratory and cardiovascular diseases. To investigate the role of arsenic in early events in vascular pathology, C57BL/6 mice ingested drinking water with or without 50 ppb sodium arsenite (AsIII) for four, five, or eight weeks. At five and eight weeks, RNA from the lungs of control and AsIII-exposed animals was processed for microarray. Sixty-five genes were significantly and differentially expressed. Differential expression of extracellular matrix (ECM) gene transcripts was particularly compelling, as 91% of genes in this category, including elastin and collagen, were significantly decreased. In additional experiments, real-time RT-PCR showed an AsIII-induced decrease in many of these ECM gene transcripts in the heart and NIH3T3 fibroblast cells. Histological stains for collagen and elastin show a distinct disruption in the ECM surrounding small arteries in the heart and lung of AsIII-exposed mice. Immunohistochemical detection of alpha-smooth muscle actin in blood vessel walls was decreased in the AsIII-exposed animals. These data reveal a functional link between AsIII exposure and disruption in the vascular ECM. These AsIII-induced early pathological events may predispose humans to respiratory and cardiovascular diseases linked to chronic low-dose AsIII exposure.
• Olsen, C. E., Liguori, A. E., Zong, Y., Lantz, R. C., Burgess, J. L., & Boitano, S. (2008). Arsenic upregulates MMP-9 and inhibits wound repair in human airway epithelial cells. American journal of physiology. Lung cellular and molecular physiology, 295(2), L293-302.
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  As part of the innate immune defense, the polarized conducting lung epithelium acts as a barrier to keep particulates carried in respiration from underlying tissue. Arsenic is a metalloid toxicant that can affect the lung via inhalation or ingestion. We have recently shown that chronic exposure of mice or humans to arsenic (10-50 ppb) in drinking water alters bronchiolar lavage or sputum proteins consistent with reduced epithelial cell migration and wound repair in the airway. In this report, we used an in vitro model to examine effects of acute exposure of arsenic (15-290 ppb) on conducting airway lung epithelium. We found that arsenic at concentrations as low as 30 ppb inhibits reformation of the epithelial monolayer following scrape wounds of monolayer cultures. In an effort to understand functional contributions to epithelial wound repair altered by arsenic, we showed that acute arsenic exposure increases activity and expression of matrix metalloproteinase (MMP)-9, an important protease in lung function. Furthermore, inhibition of MMP-9 in arsenic-treated cells improved wound repair. We propose that arsenic in the airway can alter the airway epithelial barrier by restricting proper wound repair in part through the upregulation of MMP-9 by lung epithelial cells.
• Olsen, C. E., Liguori, A. E., Zong, Y., Lantz, R. C., Burgess, J. L., & Boitano, S. A. (2008). Arsenic upregulates MMP-9 and inhibits wound repair in human airway epithelial cells. American Journal of Physiology - Lung Cellular and Molecular Physiology, 295(2), L293-L302.
• Wong, S. S., Vargas, J., Thomas, A., Fastje, C., McLaughlin, M., Camponovo, R., Lantz, R. C., Heys, J., & Witten, M. L. (2008). In vivo comparison of epithelial responses for S-8 versus JP-8 jet fuels below permissible exposure limit. Toxicology, 254(1-2), 106-11.
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  This study was designed to characterize and compare the pulmonary effects in distal lung from a low-level exposure to jet propellant-8 fuel (JP-8) and a new synthetic-8 fuel (S-8). It is hypothesized that both fuels have different airway epithelial deposition and responses. Consequently, male C57BL/6 mice were nose-only exposed to S-8 and JP-8 at average concentrations of 53mg/m(3) for 1h/day for 7 days. A pulmonary function test performed 24h after the final exposure indicated that there was a significant increase in expiratory lung resistance in the S-8 mice, whereas JP-8 mice had significant increases in both inspiratory and expiratory lung resistance compared to control values. Neither significant S-8 nor JP-8 respiratory permeability changes were observed compared to controls, suggesting no loss of epithelial barrier integrity. Morphological examination and morphometric analysis of airway tissue demonstrated that both fuels showed different patterns of targeted epithelial cells: bronchioles in S-8 and alveoli/terminal bronchioles in JP-8. Collectively, our data suggest that both fuels may have partially different deposition patterns, which may possibly contribute to specific different adverse effects in lung ventilatory function.
• Wong, S. S., Wong, S. S., Witten, M. L., Sun, N. N., Lantz, R. C., & Burgess, J. L. (2008). METHYLATION STATUS OF NEUTRAL ENDOPEPTIDASE GENES DOWN-REGULATED BY DIESEL EXHAUST PARTICULATES IN HUMAN AIRWAY EPITHELIUM. The FASEB Journal, 22.
• Zong, Y., Olsen, C. E., Liguori, A. E., Lantz, R. C., Burgess, J. L., & Boitano, S. (2008). Low-dose arsenic inhibits wound repair, upregulates MMP-9 and alters Ca2+ signaling in human airway epithelial cells. The FASEB Journal, 22.
• Lantz, R. C., Chen, G. J., Sarihan, M., Sólyom, A. M., Jolad, S. D., & Timmermann, B. N. (2007). The effect of extracts from ginger rhizome on inflammatory mediator production. Phytomedicine : international journal of phytotherapy and phytopharmacology, 14(2-3), 123-8.
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  Compounds from rhizomes of Zingiber officinale, commonly called ginger, have been purported to have anti-inflammatory actions. We have used an in vitro test system to test the anti-inflammatory activity of compounds isolated from ginger rhizome. U937 cells were differentiated and exposed to lipopolysaccharide (LPS) from Escherichia coli (1 microg/ml) in the presence or absence of organic extracts or standard compounds found in ginger (6-, 8-, 10-gingerol or 6-shogaol) for 24 h. Supernatants were collected and analyzed for the production of prostaglandin E(2) (PGE(2)) and tumor necrosis factor alpha (TNF-alpha) by standard ELISA assays. Predominant compounds in the organic extracts were identified as 6-, 8- 10-gingerols and 6-, 8-, 10-shogaols. Organic extracts or standards containing gingerols were not cytotoxic, while extracts or standards containing predominantly shogaols were cytotoxic at concentrations above 20 microg/ml. Crude organic extracts of ginger were capable of inhibiting LPS induced PGE(2) (IC(50)30 microg/ml). Thirty three fractions and subfractions, prepared by column chromatography, were analyzed for bioactivity. Extracts containing either predominantly gingerols or shogaols (identified by HPLC) were both highly active at inhibiting LPS-induced PGE(2) production (IC(50)
• Lantz, R. C., Lynch, B. J., Boitano, S., Poplin, G. S., Littau, S., Tsaprailis, G., & Burgess, J. L. (2007). Pulmonary biomarkers based on alterations in protein expression after exposure to arsenic. Environmental health perspectives, 115(4), 586-91.
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  Environmental exposure to arsenic results in multiple adverse effects in the lung. Our objective was to identify potential pulmonary protein biomarkers in the lung-lining fluid of mice chronically exposed to low-dose As and to validate these protein changes in human populations exposed to As.
• Poplin, G. S., Sturup, S., Poplin, G. S., Meza, M. M., Mcclellen, H. E., Lantz, R. C., Kopplin, M. J., Josyula, A. B., & Burgess, J. L. (2007). Environmental Arsenic Exposure and Urinary 8-OHdG in Arizona and Sonora.. Clinical toxicology (Philadelphia, Pa.), 45(5), 490-8. doi:10.1080/15563650701354119
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  Although at high levels arsenic exposure is associated with increased cancer incidence, information on the health effects of lower exposure levels is limited. The objective of this study was to determine whether arsenic at concentrations below 40 microg/L in drinking water is associated with increased urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of DNA oxidative damage and repair. Urine samples were collected from 73 nonsmoking adults residing in two communities in Arizona (mean tap water arsenic (microg/L) 4.0 +/- 2.3 and 20.3 +/- 3.7), and 51 subjects in four communities in Sonora, Mexico (mean tap water arsenic (microg/L) ranging from 4.8 +/- 0.1 to 33.3 +/- 0.6). Although urinary arsenic concentration increased with higher exposure in tap water, urinary 8-OHdG concentration did not differ by community within Arizona or Sonora, and was not associated with urinary arsenic concentration. At the exposure levels evaluated in this study, drinking water arsenic was not associated with increased DNA oxidation as measured by urinary 8-OHdG.
• Sun, N. N., Wong, S. S., Nardi, C., Ostroff, D., Witten, M. L., & Lantz, R. C. (2007). In Vitro Pro-inflammatory Regulatory role of Substance P in Alveolar Macrophages and Type II Pneumocytes after JP-8 Exposure. Journal of immunotoxicology, 4(1), 61-7.
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  The effects of JP-8 on pro-inflammatory cytokine interleukin (IL)-1alpha,beta and nitric oxide (NO) secretion as well as the role of substance P (SP) in these processes were examined in cultured alveolar macrophages (AM), type II epithelial cells (AIIE), and AM/AIIE co-cultures. Exposure of AM to JP-8 for 24 hr exhibited release of IL-1alpha,beta, whereas exposure to AIIE showed a concentration-dependent NO overproduction. Data indicate that there are cell-dependent inflammatory mechanisms responsible for the actual level of JP-8 exposure in alveoli. However, treatment with substance P significantly attenuated JP-8 induced the IL-1alpha,beta secretion. This finding was confirmed by using [Sar(9) Met (O(2))(11)] SP (10(- 10) M), an agonist of substance P, suggesting that substance P may have signal pathway(s) to AM in the inflammatory response mediated by IL-1. Moreover, AM/AIIE co-culture obviously reduced NO overproduction observed in AIIE alone, suggesting that there may be cell interactions or communications between AM and AIIE in response to the JP-8 exposure.
• Wong, S. S., Wong, S. S., Witten, M. L., Sun, N. N., Lantz, R. C., Hersh, L. B., & Burgess, J. L. (2007). Importance of neutral endopeptidase in epithelial response to diesel particulate exposure. The FASEB Journal, 21(5). doi:10.1096/fasebj.21.5.a407-c
• Funk, J. L., Frye, J. B., Oyarzo, J. N., Kuscuoglu, N., Wilson, J., McCaffrey, G., Stafford, G., Chen, G., Lantz, R. C., Jolad, S. D., Sólyom, A. M., Kiela, P. R., & Timmermann, B. N. (2006). Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis. Arthritis and rheumatism, 54(11), 3452-64.
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  Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well-characterized turmeric extract using an animal model of rheumatoid arthritis (RA).
• Funk, J. L., Oyarzo, J. N., Frye, J. B., Chen, G., Lantz, R. C., Jolad, S. D., Sólyom, A. M., & Timmermann, B. N. (2006). Turmeric extracts containing curcuminoids prevent experimental rheumatoid arthritis. Journal of natural products, 69(3), 351-5.
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  Turmeric has been used for centuries in Ayurvedic medicine as a treatment for inflammatory disorders including arthritis. On the basis of this traditional usage, dietary supplements containing turmeric rhizome and turmeric extracts are also being used in the western world for arthritis treatment and prevention. However, to our knowledge, no data are available regarding antiarthritic efficacy of complex turmeric extracts similar in composition to those available for use as dietary supplements. Therefore, the studies described here were undertaken to determine the in vivo efficacy of well-characterized curcuminoid-containing turmeric extracts in the prevention or treatment of arthritis using streptococcal cell wall (SCW)-induced arthritis, a well-described animal model of rheumatoid arthritis (RA). Arthritic index, a clinical measure of joint swelling, was used as the primary endpoint for assessing the effect of extracts on joint inflammation. An essential oil-depleted turmeric fraction containing 41% of the three major curcuminoids was efficacious in preventing joint inflammation when treatment was started before, but not after, the onset of joint inflammation. A commercial sample containing 94% of the three major curcuminoids was more potent in preventing arthritis than the essential oil-depleted turmeric fraction when compared by total curcuminoid dose per body weight. In conclusion, these data (1) document the in vivo antiarthritic efficacy of an essential oil-depleted turmeric fraction and (2) suggest that the three major curcuminoids are responsible for this antiarthritic effect, while the remaining compounds in the crude turmeric extract may inhibit this protective effect.
• Hays, A. M., Srinivasan, D., Witten, M. L., Carter, D. E., & Lantz, R. C. (2006). Arsenic and cigarette smoke synergistically increase DNA oxidation in the lung. Toxicologic pathology, 34(4), 396-404.
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  Epidemiological evidence has indicated that arsenic and cigarette smoking exposure act synergistically to increase the incidence of lung cancer. Since oxidative damage of DNA has been linked to cancer, our hypothesis is that aerosolized arsenic and cigarette smoke work synergistically to increase oxidative stress and increase DNA oxidation in the lung. To test this hypothesis male Syrian golden hamsters were exposed to room air (control), aerosolized arsenic compounds (3.2 mg/m3 for 30 minutes), cigarette smoke (5 mg/m3 for 30 minutes), or both smoke and arsenic. Exposures were for 5 days/week for 5 or 28-days. Animals were sacrificed one day after the last exposure. In the 28-day group, glutathione levels and DNA oxidation (8-oxo-2'-deoxyguanosine (8-oxo-dG)) were determined. Our results show that in the 28-day arsenic/smoke group there was a significant decrease in both the reduced and total glutathione levels compared with arsenic or smoke alone. This correlated with a 5-fold increase in DNA oxidation as shown by HPLC. Immunohistochemical localization of 8-oxo-dG showed increase staining in nuclei of airway epithelium and subadjacent interstitial cells. These results show that dual exposure of arsenic and cigarette smoke at environmentally relevant levels can act synergistically to cause DNA damage.
• Herrin, B. R., Haley, J. E., Lantz, R. C., & Witten, M. L. (2006). A reevaluation of the threshold exposure level of inhaled JP-8 in mice. The Journal of toxicological sciences, 31(3), 219-28.
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  C57BL/6 mice were nose-only exposed to JP-8 jet fuel at average concentrations of 45, 267, and 406 mg JP-8/m(3) for 1 hr/d for 7 days to further test the hypothesis that exposure to JP-8 concentrations below the current permissible exposure level (PEL) of 350 mg/m(3) will induce lung injury, and to validate a new "in-line, real-time" total hydrocarbon analysis system capable of measuring both JP-8 vapor and aerosol concentrations. Pulmonary function and respiratory permeability tests were performed 24 to 30 hr after the final exposures. No significant effects were observed at 45 or 267 mg/m(3). The only significant effect observed at 406 mg/m(3) was a decrease in inspiratory dynamic lung compliance. Morphological examination and morphometric analysis of distal lung tissue demonstrated that alveolar type II epithelial cells showed limited cellular damage with the notable exception of a significant increase in the volume density of lamellar bodies (vacuoles), which is indicative of increased surfactant production, at 45 and 406 mg/m(3). The terminal bronchial epithelium showed initial signs of cellular damage, but the morphometric analysis did not quantify these changes as significant. The morphometric analysis techniques appear to provide an increased sensitivity for detecting the deleterious effects of JP-8 as compared to the physiological evidence offered by pulmonary function or respiratory permeability tests. These observations suggest that the current 350 mg/m(3) PEL for both JP-8 jet fuel and for other more volatile petroleum distillates should be reevaluated and a lower, more accurate PEL should be established with regard human occupational exposure limits.
• Josyula, A. B., Poplin, G. S., Kurzius-Spencer, M., McClellen, H. E., Kopplin, M. J., Stürup, S., Clark Lantz, R., & Burgess, J. L. (2006). Environmental arsenic exposure and sputum metalloproteinase concentrations. Environmental research, 102(3), 283-90.
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  Exposure to arsenic in drinking water is associated with an increased rate of lung cancer. The objective of this study was to determine whether arsenic exposure at relatively low concentrations (approximately 20 microg/L) is associated with changes in biomarkers of lung inflammation, as measured by the ratio of sputum metalloproteinase and antiproteinase activity. A total of 73 subjects residing in Ajo and Tucson, Arizona were recruited for this cross-sectional study. Tap water and first morning void urine were analyzed for arsenic. Matrix metalloproteinase 2 (MMP-2), 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in induced sputum. Household tap water arsenic levels in Ajo (20.3+/-3.7 microg/L) were higher than in those Tucson (4.0+/-2.3 microg/L), as were mean urinary total inorganic arsenic levels (29.1+/-20.4 and 11.0+/-12.0 microg/L, respectively). Log-normalized MMP-2, MMP-9, and TIMP-1 concentrations in sputum were not significantly different between towns. However, after adjusting for town, asthma, diabetes, urinary monomethylarsonic acid/inorganic arsenic, and smoking history, total urinary arsenic was negatively associated with MMP-2 and TIMP-1 levels in sputum and positively associated with the ratio of MMP-2/TIMP-1 and MMP-9/TIMP-1 in sputum. Increased sputum proteinase/antiproteinase activity suggests a potential toxic mechanism for low-level arsenic exposure.
• Josyula, A. B., Poplin, G. S., Kurzius-Spencer, M., McClellen, H. E., Kopplin, M. J., Stürup, S., Lantz, R. C., & Burgess, J. L. (2006). Environmental arsenic exposure and sputum metalloproteinase concentrations. Environmental Research, 102(3), 283-290.
• Lantz, R. C., & Hays, A. M. (2006). Role of oxidative stress in arsenic-induced toxicity. Drug metabolism reviews, 38(4), 791-804.
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  Arsenic is recognized as a carcinogen for human skin, bladder, and lung, following either ingestion or inhalation; however the exact mode of action of environmentally relevant exposure has not been determined. Because arsenic in the environment exists in several oxidative states and can interact with thiols, it is thought that arsenic toxicity is mediated through oxidative stress. Production of oxygen radicals following acute in vitro exposures has been demonstrated. However, our research has chosen to focus on the role of oxidative stress following whole animal exposure to environmentally relevant doses of arsenic. Following a 28-d inhalation of arsenic or cigarette smoke or both, there was a significant decrease in both the reduced and total glutathione levels in the combined arsenic and smoke group compared to groups exposed to arsenic or smoke alone. This correlated with a 5-fold increase in DNA oxidation. Lungs processed for immunohistochemistry localization of 8-oxo-dG showed increased staining in nuclei of airway epithelium and subadjacent interstitial cells. Increases in DNA oxidation were not due to increased inflammation. Although inhalation of arsenic is an important occupational exposure, the majority of human exposures occurs through ingestion of arsenic. Our recent work has been devoted to the identification of altered pulmonary gene and protein expression following ingestion of environmentally relevant levels of arsenic in drinking water. We have found that, following chronic exposure, arsenic leads to misregulation of a number of genes and proteins in the lung. A large percentage of the altered genes and proteins are known to be regulated by redox-sensitive transcription factors, (SP1, NF kappaB, AP-1), suggesting that, at environmentally relevant levels of chronic exposure, arsenic may be acting through alteration of cellular redox status. Validation of the alterations seen in animal models of exposure is being carried out in humans.
• Jolad, S. D., Lantz, R. C., Chen, G. J., Bates, R. B., & Timmermann, B. N. (2005). Commercially processed dry ginger (Zingiber officinale): composition and effects on LPS-stimulated PGE2 production. Phytochemistry, 66(13), 1614-35.
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  Using techniques previously employed to identify ginger constituents in fresh organically grown Hawaiian white and yellow ginger varieties, partially purified fractions derived from the silica gel column chromatography and HPLC of a methylene chloride extract of commercially processed dry ginger, Zingiber officinale Roscoe, Zingiberaceae, which demonstrated remarkable anti-inflammatory activity, were investigated by gas chromatography-mass spectrometry. In all, 115 compounds were identified, 88 with retention times (R(t)) >21 min and 27 with
• Lantz, R. C., Timmermann, B. N., Solyom, A. M., Lantz, R. C., Jolad, S. D., & Chen, G. J. (2005). The effect of turmeric extracts on inflammatory mediator production.. Phytomedicine : international journal of phytotherapy and phytopharmacology, 12(6-7), 445-52. doi:10.1016/j.phymed.2003.12.011
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  Major compounds of several commonly used botanicals, including turmeric, have been purported to have anti-inflammatory actions. In order to test the anti-inflammatory activity of compounds isolated from rhizomes of Curcuma longa L. (Zingiberaceae), we have established an in vitro test system. HL-60 cells were differentiated and exposed to lipopolysaccharide (LPS) from Escherichia coli (1 microg/ml) in the presence or absence of botanical compounds for 24 h. Supernatants were collected and analyzed for the production of tumor necrosis factor alpha (TNF-alpha) and prostaglandin E2 (PGE2) using standard ELISA assays. Water-soluble extracts were not cytotoxic and did not exhibit biological activity. Organic extracts of turmeric were cytotoxic only at concentrations above 50 microg/ml. Crude organic extracts of turmeric were capable of inhibiting LPS-induced TNF-alpha (IC50 value = 15.2 microg/ml) and PGE2 (IC50 value = 0.92 microg/ml) production. Purified curcumin was more active than either demethoxy- or bisdemethoxycurcumin. Fractions and subfractions of turmeric extracts collected via preparative HPLC had differing biological activity, ranging from no activity to IC50 values of < 1 microg/ml. For some fractions, subfractionation resulted in a loss of activity, indicating interaction of the compounds within the fraction to produce an anti-inflammatory effect. A combination of several of the fractions that contain the turmeric oils was more effective than the curcuminoids at inhibiting PGE2. While curcumin inhibited COX-2 expression, turmeric oils had no effect on levels of COX-2 mRNA.
• Stearns, D. M., Yazzie, M., Bradley, A. S., Coryell, V. H., Shelley, J. T., Ashby, A., Asplund, C. S., & Lantz, R. C. (2005). Uranyl acetate induces hprt mutations and uranium-DNA adducts in Chinese hamster ovary EM9 cells. Mutagenesis, 20(6), 417-23.
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  Questions about possible adverse health effects from exposures to uranium have arisen as a result of uranium mining, residual mine tailings and use of depleted uranium in the military. The purpose of the current study was to measure the toxicity of depleted uranium as uranyl acetate (UA) in mammalian cells. The activity of UA in the parental CHO AA8 line was compared with that in the XRCC1-deficient CHO EM9 line. Cytotoxicity was measured by clonogenic survival. A dose of 200 microM UA over 24 h produced 3.1-fold greater cell death in the CHO EM9 than the CHO AA8 line, and a dose of 300 microM was 1.7-fold more cytotoxic. Mutagenicity at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) locus was measured by selection with 6-thioguanine. A dose of 200 microM UA produced approximately 5-fold higher averaged induced mutant frequency in the CHO EM9 line relative to the CHO AA8 line. The generation of DNA strand breaks was measured by the alkaline comet assay at 40 min and 24 h exposures. DNA strand breaks were detected in both lines; however a dose response may have been masked by U-DNA adducts or crosslinks. Uranium-DNA adducts were measured by inductively coupled plasma optical emission spectroscopy (ICP-OES) at 24 and 48 h exposures. A maximum adduct level of 8 U atoms/10(3) DNA-P for the 300 microM dose was found in the EM9 line after 48 h. This is the first report of the formation of uranium-DNA adducts and mutations in mammalian cells after direct exposure to a depleted uranium compound. Data suggest that uranium could be chemically genotoxic and mutagenic through the formation of strand breaks and covalent U-DNA adducts. Thus the health risks for uranium exposure could go beyond those for radiation exposure.
• Burgess, J. L., Fierro, M. A., Lantz, R. C., Hysong, T. A., Fleming, J. E., Gerkin, R., Hnizdo, E., Conley, S. M., & Klimecki, W. (2004). Longitudinal decline in lung function: Evaluation of interleukin-10 genetic polymorphisms in firefighters. Journal of Occupational and Environmental Medicine, 46(10), 1013-1022.
• Burgess, J. L., Fierro, M. A., Lantz, R. C., Hysong, T. A., Fleming, J. E., Gerkin, R., Hnizdo, E., Conley, S. M., & Klimecki, W. (2004). Longitudinal decline in lung function: evaluation of interleukin-10 genetic polymorphisms in firefighters. Journal of occupational and environmental medicine, 46(10), 1013-22.
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  During annual medical monitoring, some firefighters are found to have rates of decline in forced expiratory volume in one second (FEV1) far exceeding their peers. Interleukin-10 (IL-10) suppresses inflammation, and single nucleotide polymorphisms (SNPs) in the IL-10 gene may confer variable susceptibility to more rapid decline in lung function. In 1204 firefighters with at least six annual FEV1 measurements, increased age and greater initial FEV1 were associated with more rapid decline in lung function. DNA collected from 379 of these firefighters was screened for IL-10 SNPs at -1117, -854, 919, 1668, and 1812. A statistically significant difference in decline in lung function was found based on genotyping at the 1668 SNP. Evaluation of gene polymorphisms regulating lung inflammation may help to explain some of the variation in rate of decline in lung function in firefighters.
• Jolad, S. D., Lantz, R. C., Solyom, A. M., Chen, G. J., Bates, R. B., & Timmermann, B. N. (2004). Fresh organically grown ginger (Zingiber officinale): composition and effects on LPS-induced PGE2 production. Phytochemistry, 65(13), 1937-54.
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  Gas chromatography in conjunction with mass spectrometry, a technique previously employed to analyze non-volatile pungent components of ginger extracts modified to trimethylsilyl derivatives, was applied successfully for the first time to analyze unmodified partially purified fractions from the dichloromethane extracts of organically grown samples of fresh Chinese white and Japanese yellow varieties of ginger, Zingiber officinale Roscoe (Zingiberaceae). This analysis resulted in the detection of 20 hitherto unknown natural products and 31 compounds previously reported as ginger constituents. These include paradols, dihydroparadols, gingerols, acetyl derivatives of gingerols, shogaols, 3-dihydroshogaols, gingerdiols, mono- and diacetyl derivatives of gingerdiols, 1-dehydrogingerdiones, diarylheptanoids, and methyl ether derivatives of some of these compounds. The thermal degradation of gingerols to gingerone, shogaols, and related compounds was demonstrated. The major constituent in the two varieties was [6]-gingerol, a chemical marker for Z. officinale. Mass spectral fragmentation patterns for all the compounds are described and interpreted. Anti-inflammatory activities of silica gel chromatography fractions were tested using an in vitro PGE2 assay. Most of the fractions containing gingerols and/or gingerol derivatives showed excellent inhibition of LPS-induced PGE2 production.
• Wong, S. S., Hyde, J., Sun, N. N., Lantz, R. C., & Witten, M. L. (2004). Inflammatory responses in mice sequentially exposed to JP-8 jet fuel and influenza virus. Toxicology, 197(2), 139-47.
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  To examine the hypothesis that Jet Propulsion Fuel (JP-8) inhalation potentiates influenza virus-induced inflammatory responses, we randomly divided female C57BL/6 mice (4-weeks old, weighing approximately 24.6g) into the following groups: air control, JP-8 alone (1023 mg/m(3) of JP-8 for 1h/day for 7 days), A/Hong Kong/8/68 influenza virus (HKV) alone (a 10 microl aliquot of 2000 viral titer in the nasal passages), and a combination of JP-8 with HKV (JP-8 + HKV). The HKV alone group exhibited significantly increased total cell number/granulocyte differential in bronchoalveolar lavage fluid (BALF) compared to controls whereas the JP-8 alone group did not. The JP-8 + HKV group further exacerbated the HKV alone-induced response. However, increases in pulmonary microvascular permeability and pathological alterations in JP-8 + HKV just matched the sum of JP-8 alone- and HKV alone-induced response. Increases in BALF substance P in the JP-8 alone group and BALF leukotriene B4 or total lung compliance in the HKV alone group, respectively were similar to the changes in the JP-8 + HKV group. These findings suggest that changes in the JP-8 + HKV group may be attributed to either JP-8 inhalation or HKV treatment and indicate the different physiological responses to either JP-8 or HKV exposure. Taken together, most of the data did not provide supporting evidence that JP-8 inhalation synergizes influenza virus-induced inflammatory responses.
• Wong, S. S., Sun, N. N., Lantz, R. C., & Witten, M. L. (2004). Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation. American journal of physiology. Lung cellular and molecular physiology, 287(4), L859-66.
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  To characterize the tachykininergic effects in fire smoke (FS)-induced acute respiratory distress syndrome (ARDS), we designed a series of studies in rats. Initially, 20 min of FS inhalation induced a significant increase of substance P (SP) in bronchoalveolar lavage fluid (BALF) at 1 h and persisted for 24 h after insult. Conversely, FS disrupted 51.4, 55.6, 46.3, and 43.0% enzymatic activity of neutral endopeptidase (NEP, a primary hydrolyzing enzyme for SP) 1, 6, 12, and 24 h after insult, respectively. Immunolabeling density of NEP in the airway epithelium largely disappeared 1 h after insult due to acute cell damage and shedding. These changes were also accompanied by extensive influx of albumin and granulocytes/lymphocytes in BALF. Furthermore, levels of BALF SP and tissue NEP activity dose dependently increased and decreased, respectively, following 0, low (10 min), and high (20 min) levels of FS inhalation. However, neither the time-course nor the dose-response study observed a significant change in the highest affinity neurokinin-1 receptor (NK-1R) for SP. Finally, treatment (10 mg/kg im) with SR-140333B, an NK-1R antagonist, significantly prevented 20-min FS-induced hypoxemia and pulmonary edema 24 h after insult. Further examination indicated that SR-140333B (1.0 or 10.0 mg/kg im) fully abolished early (1 h) plasma extravasation following FS. Collectively, these findings suggest that a combination of sustained SP and NEP inactivity induces an exaggerated neurogenic inflammation mediated by NK-1R, which may lead to an uncontrolled influx of protein-rich edema fluid and cells into the alveoli as a consequence of increased vascular permeability.
• Lantz, R. C., Orozco, J., & Bogdanffy, M. S. (2003). Vinyl acetate decreases intracellular pH in rat nasal epithelial cells. Toxicological sciences : an official journal of the Society of Toxicology, 75(2), 423-31.
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  Vinyl acetate is a synthetic organic ester that has been shown to produce nasal tumors in rats following exposure to 600 ppm in air. The proposed mechanism of action involves the metabolism of vinyl acetate by carboxylesterases and the production of protons leading to cellular acidification. While vinyl acetate-induced decreases in intracellular pH (pHi) have been demonstrated in rat hepatocytes, comparable data from nasal epithelial cells do not exist. Using an in vitro assay system, we have determined the effects of vinyl acetate exposure on pHi in respiratory and olfactory nasal epithelial cells from rats. The respiratory and olfactory epithelial cells were isolated from dissected maxillo- and ethmoturbinates by enzyme digestion. The cells were plated; loaded with the pH-sensitive dye, carboxyseminaphthorhodafluor-1 (SNARF-1); and observed using confocal microscopy. Individual cellular analysis demonstrated that both respiratory and olfactory epithelial cells responded to vinyl acetate exposures with a dose-dependent decrease in pHi. Changes occurred at 100 microM but reached a plateau above 250 microM. Maximal decreases in pHi were 0.3 pH unit in respiratory epithelial cells. While pHi values were normally distributed for the respiratory epithelial cells, the olfactory epithelial cells demonstrated a bimodal distribution, indicating at least two populations of cells, with only one population of cells responding to vinyl acetate. Acidification in these cells did not plateau but continued to increase at 1000 microM. Bis(p-nitrophenyl)phosphate (BNPP), a carboxylesterase inhibitor, was able to attenuate the vinyl acetate-induced decrease in pHi. Data obtained from the isolated cells were validated using tissue explants. These results are consistent with the proposed mode of action for vinyl acetate and supply further data for developing appropriate risk assessments for vinyl acetate exposure.
• Burgess, J. L., Nanson, C. J., Hysong, T. A., Gerkin, R., Witten, M. L., & Lantz, R. C. (2002). Rapid decline in sputum IL-10 concentration following occupational smoke exposure. Inhalation Toxicology, 14(2), 133-140.
• Burgess, J. L., Nanson, C. J., Hysong, T. A., Gerkin, R., Witten, M. L., & Lantz, R. C. (2002). Rapid decline in sputum IL-10 concentration following occupational smoke exposure. Inhalation toxicology, 14(2), 133-40.
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  The acute effects of smoke exposure on inflammatory mediators such as interleukin-10 (IL-10), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha) are not well understood. Our study was designed to measure sputum concentrations of these cytokines in firefighters following low-level smoke exposure. At baseline, participating firefighters underwent blood collection, pulmonary function testing, and sputum induction through inhalation of nebulized hypertonic saline. Study participants later performed overhaul of a structural fire, during which time they wore cartridge respirators and were monitored for smoke exposure. Overhaul involves searching for and extinguishing hidden sources of combustion. One hour following overhaul, blood, pulmonary function data, and induced sputum were again collected. IL-10, IL-8, and TNF-alpha concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in sputum supernatant. In 17 firefighters, baseline sputum IL-10 concentrations were 57.0 +/- 56.8 pg/L, and declined to 16.9 +/- 27.2 pg/L following overhaul (p =.02). No significant changes were observed in sputum IL-8 and TNF-alpha concentrations. Forced vital capacity (FVC) declined significantly in study participants following overhaul. Serum concentrations of Clara-cell protein and surfactant-associated protein A increased significantly following overhaul, indicating increased lung permeability. IL-10 concentrations appear to be exquisitely sensitive to smoke, and studies of IL-10 in sputum should control for recent exposure. Reduced suppression of inflammation by IL-10 may be a mechanism by which low-level smoke exposure causes lung injury.
• Freels, J. L., Nelson, D. K., Hoyt, J. C., Habib, M., Numanami, H., Lantz, R. C., & Robbins, R. A. (2002). Enhanced activity of human IL-10 after nitration in reducing human IL-1 production by stimulated peripheral blood mononuclear cells. Journal of immunology (Baltimore, Md. : 1950), 169(8), 4568-71.
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  Nitric oxide and superoxide form the unstable compound, peroxynitrite, which can nitrate proteins and compromise function of proinflammatory cytokines at sites of inflammation. Reduced function of proinflammatory proteins such as IL-8, macrophage inflammatory protein-1alpha, and eotaxin suggest an anti-inflammatory effect of nitration. The effects of nitration on anti-inflammatory cytokines such as IL-10 are unknown. We hypothesized that peroxynitrite would modify the function of anti-inflammatory cytokines like IL-10. To test this hypothesis, the capacity of recombinant human IL-10 to inhibit production of human IL-1beta (IL-1) from LPS-stimulated human PBMC was evaluated. Human IL-10 was nitrated by incubation with peroxynitrite or by incubation with 3-morpholinosydnonimine, a peroxynitrite generator, for 2 h and then incubated with LPS-stimulated PBMC for 6 h, and IL-1 was measured in the culture supernatant fluids. Human IL-1 production was significantly lower in the peroxynitrite- or 3-morpholinosydnonimine-nitrated IL-10 group than in the IL-10 controls (p < 0.05, all comparisons). This finding demonstrates that although peroxynitrite inhibits proinflammatory cytokines, it may augment anti-inflammatory cytokines and further point to an important role for peroxynitrite in the regulation of inflammation.
• Wong, S. S., Sun, N. N., Lantz, R. C., & Witten, M. L. (2002). Tissue-specific patterns of neurokinin-1 receptor (NK-1R) gene expression in mice exposed to sidestream cigarette smoke. Toxicology and industrial health, 18(9-10), 435-44.
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  Neurokinin-1 receptor (NK-1R), a high-affinity plasma membrane-bound receptor for neurokinin substance P, plays important roles in the onset of the pathophysiological responses. To test whether the transcript levels of gene encoding NK-1R in organs are affected by sidestream cigarette smoke (SSCS) exposure, the C57BL/6 mice were randomly assigned to five groups (six/group) in a study of the dose-effect relationship. The mice were exposed to 0 (filtered room air), 2, 4, 8 and 16 mg total particulate matter (TPM) of SSCS/exposure/day, respectively, for seven days through a nose-only exposure chamber (IN-TOX, Albuquerque, NM, USA). The levels of NK-1R mRNA in the lung, heart, liver, kidney and spleen tissues were detected by reverse transcription-polymerase chain reaction (RT-PCR) techniques and normalized against GAPDH expression. NK-1R mRNA in heart tissue showed SSCS-induced dose-dependent downregulation, with minimum expression at a dose of 8.0 mg TPM. Whereas, the levels of NK-1R mRNA in the liver were upregulated to 2.86 and 5.13-fold after exposure to 2.0 and 4.0 mg TPM of SSCS respectively, then returned to 4.19 and 3.93-fold at the exposure doses of 8.0 and 16.0 mg TPM, respectively, when compared to that of the control. In the kidney, SSCS exposure at a dose of 2.0 TPM, but not higher than that level, induced significant elevation of NK-1R mRNA expression. These findings suggest that there are the paracrine and/or autocrine signalling mechanisms through receptor-ligand interactions. No alteration of NK-1R gene expression was observed in the lungs and spleen tissues in this study. The tissue-specific patterns by which SSCS affect NK-1R gene expression in these organs may partially explain dissimilarity of NK-1R activation and the associated toxicity caused by environmental tobacco smoke.
• Gandolfi, A. J., Wijeweera, J. B., Parrish, T. A., Parrish, A., Lantz, R. C., & Gandolfi, A. J. (2001). Sodium arsenite enhances AP-1 and NFkappaB DNA binding and induces stress protein expression in precision-cut rat lung slices.. Toxicological sciences : an official journal of the Society of Toxicology, 61(2), 283-94. doi:10.1093/toxsci/61.2.283
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  Arsenic is a known human carcinogen. These studies were designed to examine the impact of low arsenite concentrations on immediate early gene expression in precision-cut rat lung slices. Precision-cut lung slices are a versatile in-vitro system for toxicity studies, as they preserve the architecture and cellular heterogeneity of the lung. Since 0.1-100 microM arsenite did not compromise slice viability at 4 hours, effects of arsenite on the expression of c-jun/AP-1, NFkappaB, HSP 32, HSP 72, HSP 60, and HSP 90 were studied, using these concentrations of arsenite at 4 h. Nuclear c-jun was increased by 10 and 100 microM arsenite, while NFkappaB was not affected. Gel-shift assays indicated that 10 microM arsenite resulted in an enhanced DNA-binding activity of both AP-1 and NFkappaB. Confocal microscopic analysis of AP-1 indicated nuclear localization of this transcription factor, mainly in type-II epithelial cells and alveolar macrophages. Nuclear localization of NFkappaB was lower than that observed for AP-1, while most of the NFkappaB was localized to cytoplasm of type-II epithelial cells and alveolar macrophages. HSP 32 was increased by 1.0 and 10 microM arsenite, while HSP 72 was increased by only 100 microM arsenite. HSP 60 and HSP 90 were not changed by arsenite. These studies indicate that noncytotoxic concentrations of arsenite are capable of affecting signal transduction pathways and gene expression in the lung.
• Lemus, R., Lantz, R. C., Lange, R. W., & Karol, M. H. (2001). Rapid reduction of intracellular glutathione in human bronchial epithelial cells exposed to occupational levels of toluene diisocyanate.. Toxicological sciences : an official journal of the Society of Toxicology, 60(2), 348-55. doi:10.1093/toxsci/60.2.348
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  Toluene diisocyanate (TDI) is a recognized chemical asthmogen, yet the mechanism of this toxicity and the molecular reactions involved have not been elucidated. We have previously shown that TDI vapor forms adducts with the apical surface of the respiratory epithelium, and that it colocalizes with ciliary tubulin. In vitro, we have shown rapid reaction of TDI with glutathione (GSH) and transfer of the bisGS-TDI adduct to a sulfhydryl-containing major histocompatibility complex peptide. This study sought to determine if intracellular GSH is altered following exposure to TDI. We used the dye CellTracker Green (chloromethylfluorescein, CMFDA) for detection of glutathione. One-day and 6-day air-liquid cultures of human bronchoepithelial cells (HBE) were exposed to 20-100 ppb TDI vapor for 5, 15, or 30 min. Cells were subsequently imaged using a confocal microscope. Both 1- and 6-day cultures showed a decrease in intensity of the thiol staining as a function of the TDI exposure dose. Doses as low as 20 ppb, the current permissible exposure limit (PEL) to TDI, resulted in rapid (within 5 min) decreases in fluorescence. The decreased fluorescence was not due to cytotoxicity or decrease in either esterase or glutathione-S-transferase activity, enzymes necessary for activation of the fluorescence of CMFDA. The decrease in glutathione levels was verified using another fluorescent label, ThioGlo(TM) 1, and cell extracts. In addition, the mucus produced by 6-day air-liquid interface HBE cells in response to TDI exposure appeared to be protective, as HBE cells underlying mucus retained more fluorescence than did cells in the same cultures that were not covered with mucus. These results, along with previous data, strongly suggest that TDI enters pulmonary cells and reacts rapidly with intracellular GSH, and that this can occur at the current PEL of 20 ppb. This rapid reaction suggests the importance of cellular thiols in TDI-induced pulmonary disease.
• Quan, S. F., Ml, W., Witten, M. L., Sherrill, D. L., Quan, S. F., Nanson, C. J., Lantz, R. C., Hysong, T. A., Gerkin, R., Crutchfield, C. D., Burgess, J. L., Bolstad-johnson, D. M., & Bernard, A. M. (2001). Adverse respiratory effects following overhaul in firefighters.. Journal of occupational and environmental medicine, 43(5), 467-73. doi:10.1097/00043764-200105000-00007
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  Overhaul is the stage in which firefighters search for and extinguish possible sources of reignition. It is common practice not to wear respiratory protection during overhaul. Fifty-one firefighters in two groups, 25 without respiratory protection and 26 wearing cartridge respirators, were monitored for exposure to products of combustion and changes in spirometric measurements and lung permeability following overhaul of a structural fire. Testing at baseline and 1 hour after overhaul included forced vital capacity (FVC), forced expiratory volume in one second (FEV1), serum Clara cell protein (CC16), and serum surfactant-associated protein A (SP-A). Overhaul increased CC16 in both groups, indicating increased alveolarcapillary membrane permeability. Contrary to expectations, SP-A increased and FVC and FEV1 decreased in the firefighters wearing cartridge respirators. Changes in FEV1, CC16, and SP-A were associated with concentrations of specific products of combustion or carboxyhemoglobin levels. Firefighter exposures during overhaul have the potential to cause changes in spirometric measurements and lung permeability, and self-contained breathing apparatus should be worn during overhaul to prevent lung injury.
• Witten, M. L., Weger, N. S., Muggenburg, B. A., Lemen, R. J., Lantz, R. C., Chen, H., Bowers, M. C., Bice, D. E., & Anderson, K. A. (2000). Nedocromil sodium inhibits canine adenovirus bronchiolitis in beagle puppies.. Toxicologic pathology, 28(2), 317-25. doi:10.1177/019262330002800212
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  Nedocromil sodium is a nonsteroidal anti-inflammatory drug used to control asthmatic attacks. Our hypothesis is that nedocromil sodium inhibits virus-induced airway inflammation, a common trigger of asthma. We nebulized nedocromil sodium into beagle dogs (n = 10, mean +/- SEM ages: 149 +/- 13 days) before and after inoculation with canine adenovirus type 2 (CAV2). Control dogs (n = 10) received saline aerosols and were either infected with CAV2 (Sal/CAV2, n = 7, mean +/- SEM ages: 140 +/- 11 days) or were not infected (Sal/Sal, n = 3, ages: 143 +/- 0 days). All dogs were anesthetized with choralose (80 mg/kg i.v.), intubated, and mechanically ventilated. Pulmonary function tests and bronchoalveolar lavage (BAL) were performed using standard techniques. Pulmonary function tests revealed no significant change between the nedocromil sodium and non-nedocromil-treated groups. The percentage of infected bronchioles was quantitated as the number of inflamed airways of 40 bronchioles examined times 100 for each dog. Nedocromil-treated dogs had significantly (p < 0.05) less mucosal inflammation (mean +/- SEM, 39% +/- 5%), epithelial denudation (36% +/- 5%), and BAL neutrophilia (11 +/- 3) than did Sal/CAV2 dogs (51% +/- 6%, 57% +/- 4%, and 33% +/- 8%, respectively). We concluded that pretreatment with nedocromil sodium aerosols attenuated CAV2-induced airway inflammation in these beagle puppies.
• Young, R. S., Witten, M. L., Robledo, R. F., & Lantz, R. C. (2000). Short-term pulmonary response to inhaled JP-8 jet fuel aerosol in mice.. Toxicologic pathology, 28(5), 656-63. doi:10.1177/019262330002800504
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  B6.A.D. (Ahr(d)/Nat(s)) mice were utilized to investigate the short-term pulmonary response to JP-8 jet fuel (JP-8) aerosol inhalation. Mice were nose-only exposed to atmospheres of 0 to 118 mg/m3 for 1 h/d over a period of 7 days to further test the hypothesis that JP-8 concentrations below the permissible exposure level (PEL) of 350 mg/m3 will induce lung injury. At 24 to 30 hours after the final exposure, pulmonary function and respiratory permeability were measured on anesthetized mice and then randomly assigned for bronchoalveolar lavage or histopathology. Bronchoalveolar lavage fluid (BALF) was analyzed for total protein, lactic dehydrogenase (LDH), N-acetyl-beta-D-glucosaminidase (NAG), and cytology. Respiratory permeability increases were observed following doses of 48 and 118 mg/m3 and were supported by concomitant BALF increases in total protein and LDH. Conversely, NAG and alveolar macrophage levels decreased following the same exposure concentrations. Morphological lung injury was characterized by the targeting of bronchiolar epithelium and consisted of perivascular edema, Clara cell vacuolization, and necrosis. Alveolar injury included sporadic pulmonary edema, intra-alveolar hemorrhage, and alterations in type II epithelial cells. These results indicate that repeated inhalation of aerosolized JP-8 induces physiological, biochemical, cellular, and morphological lung injury. This study also provides evidence for the reevaluation of the 350 mg/m3 PEL for more volatile petroleum distillates with regard to respirable aerosols.
• Lantz, R. C., Witten, M. L., Wang, S., Robledo, R. F., Lantz, R. C., Hays, A. M., & Breceda, V. (1999). Early alterations of lung injury following acute smoke exposure and 21-aminosteroid treatment.. Toxicologic pathology, 27(3), 334-41. doi:10.1177/019262339902700309
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  In a simulated fire-related smoke exposure protocol, New Zealand white rabbits were utilized to investigate the potential effects of the 21-aminosteroid (lazaroid) analog U75412E on the early events of acute lung injury. Inhalation of a total of 1.6 mg/kg U75412E aerosolized at a rate of 1.53 mg/min at 0.5 hr after smoke exposure significantly attenuated the extent of lung injury at 1 hr, as evidenced by decreased bronchoalveolar lavage (BAL) concentration of total protein, 6-keto-prostaglandin F1-alpha, and blood gas defect. Histopathologic examination demonstrated that the lazaroid significantly attenuated smoke-induced lung injury as evidenced by a decrease in wet lung/body weight ratio, necrosis, and sloughing of airway epithelial cells. Electron microscopy showed that the lazaroid decreased smoke-induced interstitial edema and the vacuolization of alveolar type II epithelium (21.6 +/- 9.7 vs 8.5 +/- 3.6 vacuoled blebs/cell, smoke only vs smoke + lazaroid). However, U75412E did not attenuate smoke-induced changes in BAL concentration of tumor necrosis factor-alpha, total cell count, and granulocyte percentage. These observations suggest that U75412E may exert its action through cooperative mechanisms, such as the modulation of arachidonic acid metabolism, in addition to its characterized antioxidative effects.
• Young, S., Witten, M. L., Wang, S., Vermeulen, M. W., Robledo, R. F., Lantz, R. C., Hays, A. M., Chen, G. J., & Breceda, V. (1999). Functional alterations of alveolar macrophages subjected to smoke exposure and antioxidant lazaroids.. Toxicology and industrial health, 15(5), 464-9. doi:10.1177/074823379901500501
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  Acute inhalation of diesel fuel-polycarbonate plastic (DFPP) smoke causes severe lung injury, leading to acute respiratory distress syndrome (ARDS) and death. It has been reported that the initiation of acute lung injury is associated with the activation of pulmonary alveolar macrophages (PAM). To further explore the pathogenesis, alveolar macrophages (AM) of New Zealand rabbits ventilated and exposed to a 60 tidal volume of DFPP smoke in vivo were recovered at 1 h post-smoke. Smoke exposure induced significant increases in both mRNA and protein levels for PAM tumor necrosis factor-alpha (TNF-alpha), when compared to smoke control. Smoke also induced a biphasic response (inhibited at 2 h, enhanced at 24 h after cell isolation) in the production of superoxide (O2-) by PAM. However, aerosolized lazaroid, U75412E (1.6 mg/kg body weight), significantly attenuated smoke-induced expression in AM TNF-alpha at the protein level but not at the mRNA level, and smoke-induced changes in AM production of O2-. This study suggests that highly expressing AM TNF-alpha following smoke may be a key contributor to the cascade that establishes an acute injury process and exacerbates oxidant-derived cell injury. Whereas, the lazaroid may ameliorate smoke-induced lung injury by attenuating AM TNF-alpha release, in addition to its primary antioxidative mechanism.
• Witten, M. L., Sundareshan, P., Song, C., Rider, E. D., Mp, B., Leung, B., Lawrence, N., & Lantz, R. C. (1998). Exposure to sidestream cigarette smoke alters growth factor expression in neonatal lung. The FASEB Journal, 12(5).
• Younis, H. S., Sipes, I. G., Lantz, R. C., Hoglen, N. C., Hartley, D. P., & Gunawardhana, L. (1998). 1,2-Dichlorobenzene-induced lipid peroxidation in male Fischer 344 rats is Kupffer cell dependent.. Toxicological sciences : an official journal of the Society of Toxicology, 46(2), 376-85. doi:10.1006/toxs.1998.2523
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  1,2-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in male Fischer 344 (F344) rats and previous studies have suggested that reactive oxygen species may play a role in the development of hepatotoxicity. Since reactive oxygen species can damage lipid membranes, this study was conducted to determine the extent of lipid peroxidation after administration of 1,2-DCB by immuno-histochemical analysis of 4-hydroxynonenal (4-HNE) protein adduct formation in liver and conjugated diene formation in liver and serum. The contribution of Kupffer cells to the lipid peroxidation was also investigated. Male F344 rats were administered 1,2-DCB (3.6 mmol/kg i.p. in corn oil) and killed at selected times between 3 and 48 h. Time course studies revealed the greatest abundance of 4-HNE protein adducts in the centrilobular regions of the liver 24 h after 1,2-DCB administration, with much lower levels at 16 h. Adducts were present in necrotic and vacuolized centrilobular hepatocytes of 1,2-DCB treated rats but not in livers of controls. Further, conjugated dienes were significantly increased in liver and serum 16 and 24 h after 1,2-DCB administration, peaking at 24 h. These data correlated with hepatocellular injury, determined by serum alanine aminotransferase activity and histopathological evaluation, which was markedly elevated within 16 h and peaked at 24 h. When rats were pretreated with gadolinium chloride (GdCl3; 10 mg/kg i.v. 24 h prior to 1,2-DCB), an inhibitor of Kupffer cells, hepatotoxicity was decreased by 89 and 86%, at 16 and 24 h, respectively. Conjugated diene concentrations were decreased to control values at these times after 1,2-DCB administration. Moreover, no 4-HNE protein adducts were detected in livers of 1,2-DCB-treated rats pretreated with GdCl3. Finally, Kupffer cells isolated from 1,2-DCB-treated rats produced significantly more superoxide anion than Kupffer cells isolated from vehicle controls. These data, along with previous findings, suggest that lipid peroxidation associated with 1,2-DCB is mediated in part by Kupffer cell-derived reactive oxygen species.
• Lantz, R. C., Sobonya, R. E., Witten, M. L., Ml, W., Witten, M. L., Tollinger, B. J., Tinajero, J. P., Sobonya, R. E., Robledo, R. F., Quan, S. F., Lemen, R. J., & Lantz, R. C. (1997). Fractal analysis of lung alveoli during the acute phase vs. repair phase of an adenoviral infection in canines.. Research communications in molecular pathology and pharmacology, 95(3), 275-85.
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  Acute viral respiratory infections are commonly associated with alterations in lung growth. Recently, fractal techniques have been demonstrated to show changes in alveolar perimeter after canine adenovirus type 2 (CAV2) infection in a beagle puppy model. In the present study, we investigated whether the fractal dimension (Df) of the alveolar perimeter was changed in the acute phase (2-3 weeks after inoculation, 131d CAV2 group) or during the recovery phase (approximately 22 weeks after inoculation, 235d CAV2 group) after a single bout of CAV2. There were sham CAV2 groups, 130d and 238d controls, corresponding to the CAV2 groups. The Df of alveolar perimeter length was significantly increased in the 235d CAV2 puppies compared to all of the other beagle puppy groups. On the other hand, the fractal dimensions for alveolar perimeter length for the other beagle puppy groups were very similar. In a related human study of patients (age range of 25 h to 19 y, N = 11), who died of non-respiratory causes, showed no consistent change in Df of alveolar perimeter length with normal lung growth and development. We conclude that fractal analysis of alveolar perimeter length can be used as an index of permanent lung injury after insult to the growing lungs.
• Lantz, R. C., Witten, M. L., Lantz, R. C., Keller, R. L., & Hays, A. M. (1997). Changes in abdominal aorta wall area in rats after 14 days 45° hind limb unweighting. The FASEB Journal, 11(3).
• Pittsburgh, P., Pennsylvania, P., Lantz, R. C., & Karol, M. H. (1997). Immunohistochemical detection of toluene diisocyanate (TDI) adducts in pulmonary tissue of guinea pigs following inhalation exposure. Inhalation Toxicology, 9(2), 63-84. doi:10.1080/089583797198277
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  Toluene diisocyanate (TDI) is currently the most prevalent cause of occupational asthma. Inhalation of vapors of the reactive chemical may result in irritation and inflammation of the respiratory tract as well as in pulmonary sensitization. Although numerous studies have characterized the pulmonary inflammation, the mechanism underlying sensitization remains controversial. This investigation sought to address the problem by following the localization of TDI in the respiratory tract of guinea pigs using a well-characterized animal model that displays both immunologic and respiratory hypersensitivity to TDI. Nonanesthetized and minimally restrained guinea pigs were exposed to a sensitizing regimen of TDI that consisted of inhalation of 1.0 ppm TDI vapor for 3 h/day on 5 consecutive days. Pulmonary inflammation was present in animals sacrificed immediately following the exposure as evidenced histologically, and by increased protein and inflammatory cells in the bronchoalveolar lavage. Using a specific and se...
• Sipes, I. G., Sipes, G. I., Sauer, J. M., Mobley, S. A., Mccuskey, R. S., Lantz, R. C., Hoglen, N. C., Earnest, D. L., & Abril, E. A. (1997). Modulation of Kupffer cell and peripheral blood monocyte activity by in vivo treatment of rats with all-trans-retinol.. Liver, 17(3), 157-65. doi:10.1111/j.1600-0676.1997.tb00799.x
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  Previous studies have shown that large doses of vitamin A potentiate chemical-induced liver injury and that the Kupffer cell is directly involved in this potentiation. Therefore, these studies were designed to determine if Kupffer cells isolated from vitamin A treated male Sprague-Dawley rats (75 mg/kg/day for 3-7 days as all- trans-retinol) had altered activity and function. Respiratory activity of Kupffer cells isolated from rats treated with vitamin A for 3 to 7 days markedly increased. Similarly, phagocytic activity was significantly elevated (up to 9-fold) after exposure to vitamin A for 3 to 7 days. Production of reactive oxygen species, measured by luminol-enhanced chemiluminescence of Kupffer cells isolated after 7 days of vitamin A exposure, was significantly higher than that of control cells when stimulated with opsonized zymosan. Also, the release of superoxide anion by individual Kupffer cells isolated from vitamin A treated rats was nearly three times greater than that of control cells. Basal production of tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2) production were significantly elevated in Kupffer cells isolated from rats treated with vitamin A. Lastly, peripheral blood monocytes (PBMC) isolated from rats treated with vitamin A for 7 days had a significantly greater respiratory activity, as well as TNF-alpha and PGE2 production, than PBMC isolated from control rats. Our data suggest that large doses of vitamin A enhance both Kupffer cell and PBMC function. Upregulation of the activity by these phagocytic cells may play a role in the vitamin A potentiation of chemical-induced liver injury.
• Sobonya, R. E., Lantz, R. C., Witten, M. L., Tinajero, J. P., Sobonya, R. E., Quan, S. F., Lemen, R. J., & Lantz, R. C. (1997). Human alveolar fractal dimension in normal and chronic obstructive pulmonary disease subjects.. Research communications in molecular pathology and pharmacology, 98(2), 221-30.
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  We have determined that fractal analysis of the alveolar perimeter (Df) changes with aging in human lung tissue in twenty-nine patients, age range of 25 hours to 76 years, who died of non-respiratory related causes. There was a very significant difference (p = 0.0004) in Df between the young (less than 16 years old, N = 9, mean Df of 1.047 [0.01]) and adult (greater than 16 years old, N = 20, mean Df of 1.093 [0.013]) groups. Furthermore, there was a significant difference in Df between the Adult group and the group of patients who died of chronic obstructive pulmonary disease (COPD, N = 10) (p = 0.012). Additionally, the Df values for the COPD and cystic fibrosis (CF, N = 5) groups were virtually identical; 1.061 and 1.070, respectively. Regression analysis showed a significant (p = 0.0041) exponential relationship with a correlation coefficient of 0.59 between aging and Df. We have demonstrated that the correlation between Df and aging in humans is an exponential function and that the end-stage pulmonary diseases of COPD and CF decrease Df.
• Witten, M. L., Wang, S., Tollinger, B. J., Robledo, R. F., Rider, E. D., Lantz, R. C., Lantz, C., Hays, A. M., Dinesh, S. V., Chen, G. J., & Breceda, V. (1997). A free radical scavenger (Lazaroid U75412E) attenuates tumor necrosis factor-alpha generation in a rabbit model of smoke-induced lung injury.. Respiration; international review of thoracic diseases, 64(5), 358-63. doi:10.1159/000196704
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  The lazaroid (21-aminosteroid) analogue U75412E was evaluated in rabbits exposed to diesel fuel-polycarbonate plastic smoke. Inhalation of total of 4.6 mg U75412E aerosolized at a rate of 1.53 mg/min for 3 min before or after smoke significantly prevented or limited the extent of alveolar hypoventilation, interstitial edema, and tumor necrosis factor-alpha (TNF-alpha) by pulmonary alveolar macrophages (PAM) ex vivo observed at 2 h. The smoke-induced changes in wet lung/body weight ratios and the production of superoxide (O2-) by PAM ex vivo were also attenuated by the drug treatment after smoke exposure (p < 0.05). This study suggests that lazaroids may ameliorate the oxygen-radical-initiated cytokine processes and inflammation cascade as a result of the smoke insult.
• Witten, M. L., Tollinger, B. J., Pfaff, J. K., Lantz, R. C., Hays, A. M., & Chen, H. (1996). Neutral endopeptidase (NEP) and its role in pathological pulmonary change with inhalation exposure to JP-8 jet fuel.. Toxicology and industrial health, 12(1), 93-103. doi:10.1177/074823379601200106
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  Through a simulated flightline exposure protocol, Fischer 344 rats (F344) were subjected to an aerosol/vapor mix of the military jet fuel, JP-8. Previous studies with this model of lung injury have revealed significant increases in pulmonary resistance, increased alveolar clearance of 99mTcDTPA, and a decrease in bronchoalveolar lavage fluid (BALF) concentration of the neuropeptide substance P (SP). Exposures to JP-8 were nose-only and for one hour daily. Six groups of Fischer 344 rats were exposed for 7, 28, or 56 days at two JP-8 concentrations (low dose = 469-520 mg/m3/hr, high dose = 814-1263 mg/m3/hr). Exposed groups were matched with longitudinal controls. In response to JP-8 inhalation, exposure animals demonstrated a dose-dependent as well as duration-determined reduction in BALF SP concentration. Both JP-8 concentrations caused significant pathological changes in lower pulmonary structures.
• Witten, M. L., Wang, S., Tollinger, B. J., Tinajero, J., Robledo, R. F., Rider, E., Parliman, G., Lantz, R. C., Kunke, K., Hays, A. M., Chen, G. J., & Breceda, V. (1996). The prophylactic effects of U75412E pretreatment in a smoke-induced lung injury rabbit model.. Pharmacology & toxicology, 79(5), 231-7. doi:10.1111/j.1600-0773.1996.tb00265.x
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  The effects of the lazaroid analogue U75412E (21-[4-(3-ethylamino-2-pyridinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9]-(11)-triene-3,20-dione) were examined in an acute lung injury rabbit model. Standard doses of 0, 8 and 16 mM U75412E were aerosolized and ventilated into the lungs for 3 min. via an endotracheal tube. A 60 tidal volume dose of diesel fuel-polycarbonate plastic smoke was then instilled, followed by mechanical ventilation for one hour. Pretreatment with 16 mM U75412E significantly increased blood PaO2 and pH values, and decreased blood PaCO2 as compared to smoke only exposures. It also significantly decreased the total cell counts and granulocytes in bronchoalveolar lavage fluid, and the ability of pulmonary alveolar macrophages to produce tumour necrosis factor-alpha in vitro after cell isolation and culture. Histopathology indicated that 16 mM U75412E pretreatment attenuated increases in wet lung/body weight ratios, inflammatory focus, and interstitial oedema associated with smoke insult. In summary, U75412E pretreatment may possess the potential to improve acute smoke-induced lung injury, in part, through modulation of tumour necrosis factor-alpha production from pulmonary alveolar macrophages.
• Lantz, R. C., Witten, M. L., Tollinger, B. J., Tinajero, J., Pfaff, J. K., Parliman, G., Lantz, R. C., Hays, A. M., & Hall, J. N. (1995). Changes in lung permeability correlate with lung histology in a chronic exposure model.. Toxicology and industrial health, 11(3), 325-36. doi:10.1177/074823379501100303
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  In a simulated military flight-line exposure protocol, the effects of JP-8 jet fuel exposure on lung epithelial permeability were evaluated in male Fischer 344 rats (F344). Exposures were nose-only and for one hour daily. Groups were exposed for 7, 28, and 56 days. A protocol for administering a low dose (500mg/m3/hr) and a high dose (813-1094mg/m3/hr) of JP-8 jet fuel was used. Longitudinal sham-exposure groups (no jet fuel) for 7, 28, and 56 days were included in the protocol. Lung epithelial permeability was measured by clearance of technetium-labeled diethylenetriamine pentaacetate (99mTcDTPA, molecular weight = 492 daltons, physical half-life = 6.02 hours). The percent clearance of 99mTcDTPA per minute was calculated. Alveolar epithelial clearance for JP-8-exposed rats was dependent on both exposure concentration and duration. It was noted that at low-dose exposure concentrations alveolar epithelial clearance of 99mTcDTPA returned to low levels (LD56 = 1.09% per min; LC56 = 0.98% per min), suggesting recovery as evidenced by microscopic exam. The corresponding 56-day high-dose group (n = 10) had a significantly higher (p < 0.05) value of 2.25% per minute. The 28-day low-dose (n = 15) and high-dose (n = 20) groups had clearance values that were significantly increased from their longitudinal control group (n = 17). The alveolar epithelial permeability values were 2.51, 1.95, and 1.20, respectively. The seven-day longitudinal control, low-dose, and high-dose groups had alveolar permeability values of 1.57, 2.16, and 2.07, respectively. The lung histology correlated with the clearance values. Electron micrographs showed that all groups had interstitial edema resulting from endothelial damage. There was apparent thickening of the alveolar septa, and alveolar macrophages were activated in all groups. Lung permeability data, as determined by 99mTcDTPA alveolar clearance, indicated that lung injuries peaked at 28 days of jet fuel exposure, and this finding corresponded with the histology data. There was a discrepancy in the seven-day group between the number of cells and the 99mTcDTPA clearance values. The HD7 group had a total cell count significantly higher than all other groups, but the 99mTcDTPA clearance values in that group were not significantly different from that of any other group.
• Pfaff, J. K., Witten, M. L., Pfaff, J., Parton, K., Lantz, R. C., Hays, A. M., & Chen, H. (1995). Inhalation exposure to JP-8 jet fuel alters pulmonary function and substance P levels in Fischer 344 rats.. Journal of applied toxicology : JAT, 15(4), 249-56. doi:10.1002/jat.2550150404
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  In a simulated military flightline exposure protocol, Fischer 344 rats (F344) were used to investigate the pulmonary effects of JP-8 jet fuel inhalation. Exposures were nose only and for 1 h daily. Groups were exposed for 7 days (7D) or 28 days (28D). Each exposure group had a matched longitudinal control group (LC7 and LC28). Exposure concentrations of 520 mg m-3 caused an increase in dynamic compliance after 7 days of exposure, but compliance changes were not seen with continued exposure (28D, 495 mg m-3). Pulmonary resistance was increased in both 7- and 28-day JP-8-exposed groups. Changes in pulmonary function were accompanied by a decrease in substance P concentrations from the bronchoalveolar lavage fluid (BALF). No significant change was observed in BALF levels of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, which is a marker of endothelial cell function. The JP-8-exposed rats gained significantly less weight during the study period than the LC7 and LC28 groups, and the lungs of the 7D group were heavier by wet lung/body weight ratio (WtL/WtB). Alveolar clearance of technetium-labelled diethylenetriamine pentaacetate ([99mTc]DTPA) was increased in jet fuel-exposed groups. Light microscopy showed no pathological evidence of lung injury. Recovery from the early pulmonary effects of JP-8 inhalation occurred with continued exposure, as seen by recovery of pulmonary compliance and WtL/WtB.
• Parliman, G., Lantz, R. C., Chen, G. J., & Carter, D. E. (1994). Effect of arsenic exposure on alveolar macrophage function. I. Effect of soluble as(III) and as(V).. Environmental research, 67(2), 183-95. doi:10.1006/enrs.1994.1073
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  Despite potential differences in the mechanism and potency of toxicity between the two common oxidation states of arsenic (As(III) and As(V)), assessments of the risk from inhaled arsenic generally ignore the oxidation state of inorganic arsenicals. Differences between potency and toxicity of As(III) and As(V) were evaluated by determining alteration in function of pulmonary alveolar macrophages (PAM) following in vivo and in vitro exposure to soluble arsenic. Male Sprague-Dawley rats were used throughout. One day following intratracheal instillation of 1 mg/ml (as arsenic) of either sodium arsenite (As(III)) or sodium arsenate (As(V)), PAM were lavaged and analyzed for alterations in superoxide (O2-), prostaglandin E2 (PGE2), and tumor necrosis factor (TNF-alpha) production. There were no differences in bronchoalveolar lavage fluid PGE2 or TNF-alpha. PAM lavaged from As(V)-exposed animals showed significant increases in O2- production. In vivo exposure to either oxidative form of arsenic decreased basal and lipopolysaccharide (LPS)-induced release of TNF-alpha production by PAM, but did not suppress LPS-induced production of PGE2. To test the direct effects of arsenic on PAM function, PAM were lavaged from control animals and exposed, in vitro, to either arsenical for up to 24 hr to concentrations of 0.1 to 300 micrograms/ml arsenic. Doses used were not cytotoxic to PAM, since LDH release was not significantly increased, even at the highest dose. Significant dose-dependent inhibition of O2- production was only evident after 24 hr exposure to arsenicals. As(III) was more potent than As(V), inhibiting O2- at concentrations as low as 0.1 micrograms/ml compared to 1.0 micrograms/ml of As(V). Suppression of LPS-induced release of TNF-alpha also occurred at lower concentrations of As(III), 50% inhibition at 0.15 micrograms/ml, compared to As(V), 50% inhibition at 1.8 micrograms/ml. While As(III) exposure had no affect on PGE2 production, As(V) caused inhibition of LPS-induced PGE2 production at concentrations above 1.0 micrograms/ml. Differences between As(III) and As(V) indicate that different mechanisms and/or potencies exist between the two arsenic species. Arsenic-induced alteration in PAM function may compromise host defense against infections and alter immune surveillance.
• Witten, M. L., Rodd, A., Quan, S. F., Lemen, R. J., Leeman, S. E., Lantz, R. C., Kage, R., Dey, R. D., Chen, H., & Bowers, M. C. (1993). Nedocromil preserves neuropeptides in neurons associated with airway smooth muscle and reduces adenovirus-induced airway hyperreactivity.. Regulatory peptides, 46(1-2), 211-3. doi:10.1016/0167-0115(93)90036-8
• Quan, S. F., Sobonya, R. E., Witten, M. L., Sobonya, R. E., Quan, S. F., Lemen, R. J., Lantz, R. C., & Grad, R. (1992). Effects of respiratory viruses on pulmonary alveolar macrophages.. Pediatric pulmonology, 12(2), 105-12. doi:10.1002/ppul.1950120209
• Witten, M. L., Lazarus, D. S., Lantz, R. C., Jung, W. K., Joseph, P. M., & Hales, C. A. (1992). Chronic Sidestream Cigarette Smoke Exposure Causes Lung Injury in Rabbits. Indoor and Built Environment, 1(6), 341-347. doi:10.1177/1420326x9200100605
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  The effects of sidestream cigarette smoke (SSCS) (a 15-min exposure per day for 20 days) were determined on markers of lung injury in New Zealand white rabbits (n = 9) and a control group (n = 6). The SSCS consisted of air and smoke which were aspirated by syringe from a funnel inverted over a lit ciga rette. The rabbits were placed in an environmental chamber into which 3 liters of SSCS were injected over a 15-min period each day. Chronic SSCS caused an increase (p < 0.05) in pulmonary epithelial clearance (k) of technetium labeled diethylenetriamine pentaacetate (99mTcDTPA); k = 0.83 (±0.07) for the SSCS-exposed group and 0.66 (± 0.02) for the control group. This increase in lung permeability was accompanied by an increase in bronchoalveolar lavage (BAL) white cell count; SSCS = 83,353 ( ± 11,954) cells/mm3 BAL fluid versus control = 16,450 (± 6,683) cells/mm3 BAL fluid and an increase in BAL leukotriene E4; SSCS = 742 (± 285) pg/ml BAL fluid compared with 76 (± 2) pg/ml BAL fluid for controls. Cultured...
• Witten, M. L., Pfaff, J. K., Parton, K. H., Leeman, S. E., Lantz, R. C., Kage, R., Hays, A. M., & Chen, H. (1992). Capsaicin pretreatment before JP-8 jet fuel exposure causes a large increase in airway sensitivity to histamine in rats☆. Regulatory Peptides, 37, S176. doi:10.1016/0167-0115(92)91031-t
• Lantz, R. C., Keller, G. E., & Burrell, R. (1991). The role of platelet-activating factor in the pulmonary response to inhaled bacterial endotoxin.. The American review of respiratory disease, 144(1), 167-72. doi:10.1164/ajrccm/144.1.167
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  Quantitative morphometric analyses were carried out on animals subjected to aerosols of bacterial endotoxin (LPS) to further define the role of platelet-activating factor (PAF) in the development of pulmonary injury. Hamsters were exposed to either saline aerosol or dilute aerosols of LPS (4 micrograms/m3) for standard lengths of time. Within each aerosol exposure group, animals were further subdivided into groups receiving either the PAF receptor binding antagonist, RP 48740, or saline injections. LPS inhalation resulted in decreased fixed lung volume, increased sequestration of polymorphonuclear leukocytes and platelets in pulmonary capillaries, increased type I epithelial and endothelial cellular volumes, increased cellular interstitium, and increased endothelial pinocytotic vesicles. Treatment with RP 48740 either attenuated or abolished the ability of inhaled LPS to induce these structural alterations. The PAF antagonist also inhibited LPS-induced increases in pulmonary capillary permeability. It is concluded that PAF is one of the major injury-promoting mediators released upon inhalation exposure to environmentally realistic concentrations of bacterial endotoxin. A major but not exclusive target of this mediator is the pulmonary vascular endothelium.
• Witten, M. L., Seidner, S., S, S., Quan, S. F., Lemen, R. J., Lantz, R. C., Hubbard, A. K., Grad, R., & Ak, H. (1991). Effect of smoke inhalation on immediate changes in lung chemical mediators.. Research communications in chemical pathology and pharmacology, 74(3), 259-72.
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  We studied the effects of acute smoke exposure on lung and alveolar macrophage (AM) function in New Zealand white rabbits. Six rabbits were exposed to smoke (SE, N = 6) and a control group of rabbits (SS, N = 6) were exposed to sham smoke. The smoke exposure consisted of 60 tidal volume breaths of air and smoke which were aspirated by syringe from a sampling port of a smoke chamber. The smoke was generated by the combustion of 20 ml diesel fuel and 0.2 g polycarbonate plastic shavings. The smoke was administered in 8-9 min. The rabbits were then killed and the lungs were removed for lavage. Acute smoke exposure caused a significant (p = 0.037) increase in bronchoalveolar lavage fluid levels of leukotriene B4 in the SE rabbits; 643 (+/- 30, SEM) pg/ml compared to 539 (+/- 43, SEM) pg/ml for SS rabbits at 3-4 min post-exposure. Lung surfactant, measured as mumoles/kg phosphatidylcholine, was decreased (p = 0.039) in SE rabbits' bronchoalveolar lavage fluid, 1.07 (+/- 0.12, SEM) -vs- 1.45 (+/- 0.15, SEM) for SS. Furthermore, cultured SE alveolar macrophage superoxide secretion after stimulation with phorbol myristate acetate was significantly decreased versus SS alveolar macrophage superoxide values at 40 min in culture. We conclude that acute smoke exposure causes immediate increases in bronchoalveolar lavage fluid levels of LTB4, and decreases in alveolar macrophage superoxide production and lung surfactant. These changes in chemical mediators may contribute to the lung injury caused by the smoke insult.
• Sobonya, R. E., Lantz, R. C., L, D., Ml, W., Witten, M. L., Sobonya, R. E., Quan, S. F., Lentz, L. A., Lemen, R. J., Lantz, R. C., Hubbard, A. K., Grad, R., & Devine, L. C. (1990). Piriprost pretreatment attenuates the smoke-induced increase in 99mTcDTPA lung clearance.. Experimental lung research, 16(4), 339-53. doi:10.3109/01902149009108849
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  We studied the effects of acute smoke exposure on lung permeability, eicosanoids, and inflammatory cell activity. Thirty-five New Zealand white rabbits were anesthetized, paralyzed, and exposed to 60 tidal volume breaths of diesel fuel-polycarbonate plastic smoke or sham smoke within 10 min. At 1 h postexposure the rabbits were killed and their lungs were removed for bronchoalveolar lavage (BAL) or pathologic procedures. Smoke exposure caused decreases in technetium-labeled diethylenetriamine pentaacetate (99mTcDTPA, mol. wt. 492 Da) biological half-life (t1/2), BAL plasminogen activator, and BAL leukotriene B4 (LTB4). In addition, alveolar macrophage acid phosphatase enzyme activity increased in smoke-exposed rabbits. The leukotriene synthesis inhibitor, piriprost (U-60,257), given before smoke exposure, caused attenuation of the changes in 99mTcDTPA uptake and plasminogen activator, swelling of type I alveolar cell epithelium, a large increase in lung inflammatory cells, and decreases in BAL LTB4, prostaglandin E2 (PGE2), and TxB2 (stable metabolite of thromboxane, TxA2). We conclude that changes in alveolar-capillary barrier permeability and plasminogen activator activity occur within 1 h after exposure to smoke and may play an early role in the inflammatory process associated with smoke inhalation injury. Furthermore, piriprost attenuates the smoke-induced increase in alveolar-capillary barrier permeability and decrease in plasminogen activator activity and causes a swelling of type I alveolar epithelium. However, our data suggest that neither lung eicosanoids or the alveolar macrophage lysis process plays a major role in the smoke-induced increase in alveolar-capillary barrier permeability.
• Lantz, R. C., Hinton, D. E., & Hampton, J. A. (1989). Functional units in rainbow trout (Salmo gairdneri, Richardson) liver: III. Morphometric analysis of parenchyma, stroma, and component cell types.. The American journal of anatomy, 185(1), 58-73. doi:10.1002/aja.1001850107
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  Hepatic stroma and parenchyma with its component cell types were quantitatively described in adult male and female actively-spawning 5-year-old rainbow trout (Salmo gairdneri, Richardson). Point-count morphometry of glycol methacrylate sections estimated volume compartments for stroma and parenchyma. Veins composed 85% of the stroma while arteries and bile ducts occupied approximately 6-7% each. Parenchyma accounted for 95% of hepatic volume. Point-count morphometry of transmission electron micrographs estimated volume compartments as well as numerical and surface density measurements for parenchymal components. Within the hepatic parenchymal compartment, hepatocytes occupied 85% and showed significant sex differences. Female hepatocytes were significantly more numerous but were smaller, only 60% of the volume of male hepatocytes. Since hepatocyte nuclear volume was equal in both sexes, differences were due to reduced cytoplasmic volume in females. Perisinusoidal macrophages of females occupied larger volumes of their respective parenchymal compartments, and their larger mean cytoplasmic volumes suggested activation. Biliary epithelial cells of preductules and ductules were numerous. Ratios of numerical density of hepatocytes to biliary epithelial cells were consistent with a tubular arrangement of hepatocytes. Factors possibly mediating the sexual dimorphism are discussed.
• Mccuskey, R. S., Mccuskey, P. A., Lauren, D. J., Lantz, R. C., & Hinton, D. E. (1989). In vivo microscopy of liver microvasculature in rainbow trout (Oncorhynchus mykiss). Marine Environmental Research, 28(1-4), 407-410. doi:10.1016/0141-1136(89)90270-5
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  Abstract Morphological change is an excellent biomarker of exposure to toxicants because it is the integration of biochemical and physiological injury. Zonal patterns of necrosis in the liver have also allowed mammalian pathologists to suggest the mechanism of toxicity for certain compounds. Unfortunately, the necrotic patterns in fish are not well understood because we cannot unequivocally identify portal (afferent) from hepatic (efferent) venules in histologic sections. In vivo microscopy does allow such analysis. Mature trout were surgically implanted with dorsal aortic and portal vein catheters, and in vivo microscopy of the liver surface performed through a window in the side of anesthetized, artificially ventilated animals. Blood flow patterns were recorded on video tape by injecting fluorescein solutions. Video images were digitized and superimposed to reveal the interaction between arterial and venous vessels. We found a repeating pattern of alternation between afferent and efferent regions of the microvascular bed. The hepatic parenchyma near the convex laterorostral surface is drained by superficially placed hepatic venules. Afferent venules reach this area by passing from deeper within the liver. Arteriole distribution appeared to closely parallel portal venule distribution. Melanomacrophages were associated with arterioles. Many of these characteristics are common with the mammalian liver. However, correlation of the dimensions of cells and vascular elements between histologic sections and in vivo images are needed before we can assign terms such as periportal or pericentral to routine histologic analyses.

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• Lantz, R. C., Chief, K., & Maier, R. M. (2016, April). University of Arizona programs on environmental health and mining impacts in native populations. "University of Arizona programs on environmental health and mining impacts in native populations" written and oral testimony provided to a Senate field hearing (chaired by Senators Barrasso and McCain): “Examining EPA’s Unacceptable Response to Indian Tribes”. City of Phoenix Council Chambers, Phoenix, AZ,.