Xiaoguang Sun

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• Ahmed, M., Casanova, N. G., Zaghloul, N., Gupta, A., Rodriguez, M., Robbins, I. R., Kempf, C. L., Sun, X., Song, J. H., Hernon, V. R., Sammani, S., Camp, S. M., Moreira, A., Hsu, C. D., & Garcia, J. G. (2023). The eNAMPT/TLR4 inflammatory cascade drives the severity of intra-amniotic inflammation in pregnancy and predicts infant outcomes. Frontiers in physiology, 14, 1129413.
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  Intra-amniotic inflammation (IAI) or chorioamnionitis is a common complication of pregnancy producing significant maternal morbidity/mortality, premature birth and neonatal risk of chronic lung diseases such as bronchopulmonary dysplasia (BPD). We examined eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a critical inflammatory DAMP and TLR4 ligand, as a potential therapeutic target to reduce IAI severity and improve adverse fetal/neonatal outcomes. Blood/tissue samples were examined in: 1) women with histologically-proven chorioamnionitis, 2) very low birth weight (VLBW) neonates, and 3) a preclinical murine pregnancy model of IAI. Groups of pregnant IAI-exposed mice and pups were treated with an eNAMPT-neutralizing mAb. Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased expression in whole blood from VLBW neonates (day 5) significantly predicted BPD development. Compared to untreated LPS-challenged murine dams (gestational day 15), pups born to eNAMPT mAb-treated dams (gestational days 15/16) exhibited a > 3-fold improved survival, reduced neonate lung eNAMPT/cytokine levels, and reduced development and severity of BPD and pulmonary hypertension (PH) following postnatal exposure to 100% hyperoxia days 1-14. Genome-wide gene expression studies of maternal uterine and neonatal cardiac tissues corroborated eNAMPT mAb-induced reductions in inflammatory pathway genes. The eNAMPT/TLR4 inflammatory pathway is a highly druggable contributor to IAI pathobiology during pregnancy with the eNAMPT-neutralizing mAb a novel therapeutic strategy to decrease premature delivery and improve short- and long-term neonatal outcomes. eNAMPT blood expression is a potential biomarker for early prediction of chronic lung disease among premature neonates.
• Lynn, H., Sun, X., Casanova, N., Christian Bime1, C., Oita, R., Ramos, N., Wurfel, M., Meduri, G., Christiani, D., Coletta, D., Camp, S., Bedrick, E., Karnes, J., Lussier, Y., Ellis, N., & Garcia, J. G. (2023). Linkage of NAMPT promoter variants to eNAMPT secretion, plasma eNAMPT levels and ARDS severity. Therapeutic Advances in Respiratory Disease. doi:DOI: 10.1177/17534666231181262
• Sun, X., Sammani, S., Hufford, M., Sun, B. L., Kempf, C. L., Camp, S. M., Garcia, J. G., & Bime, C. (2023). Targeting SELPLG/ P-selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter. Pulmonary Circulation. doi:DOI: 10.1002/PUL2.12206
• Sun, X., Sun, B., Kempf, C., Song, J., Casanova, N., Camp, S., Hernon, V., Fallon, M., Bime, C., Martin, D., Travelli, C., Zhang, D., & Garcia, J. G. (2023). Involvement of eNAMPT/TLR4 Inflammatory Signaling in Progression of Non-Alcoholic Fatty Liver Disease, Steatohepatitis and Fibrosis. FASEB J. doi:DOI: 10.1096/FJ.202201972RR
• Belvitch, P., Casanova, N., Sun, X., Camp, S. M., Sammani, S., Brown, M. E., Mascarhenas, J., Lynn, H., Adyshev, D., Siegler, J., Desai, A., Seyed-Saadat, L., Rizzo, A., Bime, C., Shekhawat, G. S., Dravid, V. P., Reilly, J. P., Jones, T. K., Feng, R., , Letsiou, E., et al. (2022). A cortactin CTTN coding SNP contributes to lung vascular permeability and inflammatory disease severity in African descent subjects. Translational research : the journal of laboratory and clinical medicine, 244, 56-74.
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  The cortactin gene (CTTN), encoding an actin-binding protein critically involved in cytoskeletal dynamics and endothelial cell (EC) barrier integrity, contains single nucleotide polymorphisms (SNPs) associated with severe asthma in Black patients. As loss of lung EC integrity is a major driver of mortality in the Acute Respiratory Distress Syndrome (ARDS), sepsis, and the acute chest syndrome (ACS), we speculated CTTN SNPs that alter EC barrier function will associate with clinical outcomes from these types of conditions in Black patients. In case-control studies, evaluation of a nonsynonymous CTTN coding SNP Ser484Asn (rs56162978, G/A) in a severe sepsis cohort (725 Black subjects) revealed significant association with increased risk of sepsis mortality. In a separate cohort of sickle cell disease (SCD) subjects with and without ACS (177 SCD Black subjects), significantly increased risk of ACS and increased ACS severity (need for mechanical ventilation) was observed in carriers of the A allele. Human lung EC expressing the cortactin S484N transgene exhibited: (i) delayed EC barrier recovery following thrombin-induced permeability; (ii) reduced levels of critical Tyr486 cortactin phosphorylation; (iii) inhibited binding to the cytoskeletal regulator, nmMLCK; and (iv) attenuated EC barrier-promoting lamellipodia dynamics and biophysical responses. ARDS-challenged Cttn+/- heterozygous mice exhibited increased lung vascular permeability (compared to wild-type mice) which was significantly attenuated by IV delivery of liposomes encargoed with CTTN WT transgene but not by CTTN S484N transgene. In summary, these studies suggest that the CTTN S484N coding SNP contributes to severity of inflammatory injury in Black patients, potentially via delayed vascular barrier restoration.
• Casanova, N. G., Reyes-Hernon, V., Gregory, T., Sun, B., Bermudez, T., Hufford, M. K., Oita, R. C., Camp, S. M., Hernandez-Molina, G., Serrano, J. R., Sun, X., Fimbres, J., Mirsaeidi, M., Sammani, S., Bime, C., & Garcia, J. G. (2022). Biochemical and genomic identification of novel biomarkers in progressive sarcoidosis: HBEGF, eNAMPT, and ANG-2. Frontiers in medicine, 9, 1012827.
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  Progressive pulmonary fibrosis is a serious complication in subjects with sarcoidosis. The absence of reliable, non-invasive biomarkers that detect early progression exacerbates the difficulty in predicting sarcoidosis severity. To potentially address this unmet need, we evaluated a panel of markers for an association with sarcoidosis progression (HBEGF, NAMPT, IL1-RA, IL-6, IL-8, ANG-2). This panel encompasses proteins related to inflammation, vascular injury, cell proliferation, and fibroblast mitogenesis processes.
• Garcia, A. N., Casanova, N. G., Kempf, C. L., Bermudez, T., Valera, D. G., Song, J. H., Sun, X., Cai, H., Moreno-Vinasco, L., Gregory, T., Oita, R. C., Hernon, V. R., Camp, S. M., Rogers, C., Kyubwa, E. M., Menon, N., Axtelle, J., Rappaport, J., Bime, C., , Sammani, S., et al. (2022). eNAMPT Is a Novel Damage-associated Molecular Pattern Protein That Contributes to the Severity of Radiation-induced Lung Fibrosis. American journal of respiratory cell and molecular biology, 66(5), 497-509.
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  The paucity of therapeutic strategies to reduce the severity of radiation-induced lung fibrosis (RILF), a life-threatening complication of intended or accidental ionizing radiation exposure, is a serious unmet need. We evaluated the contribution of eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a damage-associated molecular pattern (DAMP) protein and TLR4 (Toll-like receptor 4) ligand, to the severity of whole-thorax lung irradiation (WTLI)-induced RILF. Wild-type (WT) and heterozygous C57BL6 mice and nonhuman primates (NHPs, ) were exposed to a single WTLI dose (9.8 or 10.7 Gy for NHPs, 20 Gy for mice). WT mice received IgG (control) or an eNAMPT-neutralizing polyclonal or monoclonal antibody (mAb) intraperitoneally 4 hours after WTLI and weekly thereafter. At 8-12 weeks after WTLI, NAMPT expression was assessed by immunohistochemistry, biochemistry, and plasma biomarker studies. RILF severity was determined by BAL protein/cells, hematoxylin and eosin, and trichrome blue staining and soluble collagen assays. RNA sequencing and bioinformatic analyses identified differentially expressed lung tissue genes/pathways. NAMPT lung tissue expression was increased in both WTLI-exposed WT mice and NHPs. mice and eNAMPT polyclonal antibody/mAb-treated mice exhibited significantly attenuated WTLI-mediated lung fibrosis with reduced: ) NAMPT and trichrome blue staining; ) dysregulated lung tissue expression of smooth muscle actin, p-SMAD2/p-SMAD1/5/9, TGF-β, TSP1 (thrombospondin-1), NOX4, IL-1β, and NRF2; ) plasma eNAMPT and IL-1β concentrations; and ) soluble collagen. Multiple WTLI-induced dysregulated differentially expressed lung tissue genes/pathways with known tissue fibrosis involvement were each rectified in mice receiving eNAMPT mAbs.The eNAMPT/TLR4 inflammatory network is essentially involved in radiation pathobiology, with eNAMPT neutralization an effective therapeutic strategy to reduce RILF severity.
• Garcia, A. N., Casanova, N. G., Valera, D. G., Sun, X., Song, J. H., Kempf, C. L., Moreno-Vinasco, L., Burns, K., Bermudez, T., Valdez, M., Cuellar, G., Gregory, T., Oita, R. C., Hernon, V. R., Barber, C., Camp, S. M., Martin, D., Liu, Z., Bime, C., , Sammani, S., et al. (2022). Involvement of eNAMPT/TLR4 signaling in murine radiation pneumonitis: protection by eNAMPT neutralization. Translational research : the journal of laboratory and clinical medicine, 239, 44-57.
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  Therapeutic strategies to prevent or reduce the severity of radiation pneumonitis are a serious unmet need. We evaluated extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, as a therapeutic target in murine radiation pneumonitis. Radiation-induced murine and human NAMPT expression was assessed in vitro, in tissues (IHC, biochemistry, imaging), and in plasma. Wild type C57Bl6 mice (WT) and Nampt heterozygous mice were exposed to 20Gy whole thoracic lung irradiation (WTLI) with or without weekly IP injection of IgG (control) or an eNAMPT-neutralizing polyclonal (pAb) or monoclonal antibody (mAb). BAL protein/cells and H&E staining were used to generate a WTLI severity score. Differentially-expressed genes (DEGs)/pathways were identified by RNA sequencing and bioinformatic analyses. Radiation exposure increases in vitro NAMPT expression in lung epithelium (NAMPT promoter activity) and NAMPT lung tissue expression in WTLI-exposed mice. Nampt mice and eNAMPT pAb/mAb-treated mice exhibited significant histologic attenuation of WTLI-mediated lung injury with reduced levels of BAL protein and cells, and plasma levels of eNAMPT, IL-6,  and IL-1β. Genomic and biochemical studies from WTLI-exposed lung tissues highlighted dysregulation of NFkB/cytokine and MAP kinase signaling pathways which were rectified by eNAMPT mAb treatment. The eNAMPT/TLR4 pathway is essentially involved in radiation pathobiology with eNAMPT neutralization an effective therapeutic strategy to reduce the severity of radiation pneumonitis.
• Sammani, S., Bermudez, T., Kempf, C. L., Song, J. H., Fleming, J. C., Reyes Hernon, V., Hufford, M., Tang, L., Cai, H., Camp, S. M., Natarajan, V., Jacobson, J. R., Dudek, S. M., Martin, D. R., Karmonik, C., Sun, X., Sun, B., Casanova, N. G., Bime, C., & Garcia, J. G. (2022). eNAMPT Neutralization Preserves Lung Fluid Balance and Reduces Acute Renal Injury in Porcine Sepsis/VILI-Induced Inflammatory Lung Injury. Frontiers in physiology, 13, 916159.
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  Numerous potential ARDS therapeutics, based upon preclinical successful rodent studies that utilized LPS challenge without mechanical ventilation, have failed in Phase 2/3 clinical trials. Recently, ALT-100 mAb, a novel biologic that neutralizes the TLR4 ligand and DAMP, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), was shown to reduce septic shock/VILI-induced porcine lung injury when delivered 2 h after injury onset. We now examine the ALT-100 mAb efficacy on acute kidney injury (AKI) and lung fluid balance in a porcine ARDS/VILI model when delivered 6 h post injury. Compared to control PBS-treated pigs, exposure of ALT-100 mAb-treated pigs (0.4 mg/kg, 2 h or 6 h after injury initiation) to LPS-induced pneumonia/septic shock and VILI (12 h), demonstrated significantly diminished lung injury severity (histology, BAL PMNs, plasma cytokines), biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue ratios, ultrasound-derived B lines, and chest radiograph opacities. Delayed ALT-100 mAb at 2 h was significantly more protective than 6 h delivery only for plasma eNAMPT while trending toward greater protection for remaining inflammatory indices. Delayed ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats when delivered up to 12 h after LPS. These studies indicate the delayed delivery of the eNAMPT-neutralizing ALT-100 mAb reduces inflammatory lung injury, preserves lung fluid balance, and reduces multi-organ dysfunction, and may potentially address the unmet need for novel therapeutics that reduce ARDS/VILI mortality.
• Ahmed, M., Zaghloul, N., Zimmerman, P., Casanova, N. G., Sun, X., Song, J. H., Hernon, V. R., Sammani, S., Rischard, F., Rafikova, O., Rafikov, R., Makino, A., Kempf, C. L., Camp, S. M., Wang, J., Desai, A. A., Lussier, Y., Yuan, J. X., & Garcia, J. G. (2021). Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb. Pulmonary circulation, 11(4), 20458940211059712.
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  Pharmacologic interventions to halt/reverse the vascular remodeling and right ventricular dysfunction in pulmonary arterial hypertension (PAH) remains an unmet need. We previously demonstrated extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a DAMP (damage-associated molecular pattern protein) contributing to PAH pathobiology via TLR4 ligation. We examined the role of endothelial cell (EC)-specific eNAMPT in experimental PH and an eNAMPT-neutralizing mAb as a therapeutic strategy to reverse established PH. Hemodynamic/echocardiographic measurements and tissue analyses were performed in Sprague Dawley rats exposed to 10% hypoxia/Sugen (three weeks) followed by return to normoxia and weekly intraperitoneal delivery of the eNAMPT mAb (1 mg/kg). WT C57BL/6J mice and conditional EC-cNAMPT mice were exposed to 10% hypoxia (three weeks). Biochemical and RNA sequencing studies were performed on rat PH lung tissues and human PAH PBMCs. Hypoxia/Sugen-exposed rats exhibited multiple indices of severe PH (right ventricular systolic pressure, Fulton index), including severe vascular remodeling, compared to control rats. PH severity indices and plasma levels of eNAMPT, IL-6, and TNF- were all significantly attenuated by eNAMPT mAb neutralization. Compared to hypoxia-exposed WT mice, cNAMPT KO mice exhibited significantly reduced PH severity and evidence of EC to mesenchymal transition (EndMT). Finally, biochemical and RNAseq analyses revealed eNAMPT mAb-mediated rectification of dysregulated inflammatory signaling pathways (TLR/NF-κB, MAP kinase, Akt/mTOR) and EndMT in rat PH lung tissues and human PAH PBMCs. These studies underscore EC-derived eNAMPT as a key contributor to PAH pathobiology and support the eNAMPT/TLR4 inflammatory pathway as a highly druggable therapeutic target to reduce PH severity and reverse PAH.
• Sun, B. L., Tang, L., Sun, X., Garcia, A. N., Camp, S. M., Posadas, E., Cress, A. E., & Garcia, J. G. (2021). A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression. Pharmaceuticals (Basel, Switzerland), 14(12).
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  Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. In the current study, we further investigate the therapeutic effects of an eNAMPT-neutralizing humanized monoclonal antibody (ALT-100 mAb) in preclinical PCa orthotopic xenograft models. We utilized human aggressive PCa cells (DU145 or PC3) for prostate implantation in SCID mice receiving weekly intraperitoneal injections of either ALT-100 mAb or IgG/PBS (control) for 12 weeks. Prostatic tumors and solid organs were examined for tumor growth, invasion, and metastasis and for biochemical and immunohistochemistry evidence of NFκB activation. ALT-100 mAb treatment significantly improved overall survival of SCID mice implanted with human PCa orthotopic prostate xenografts while inducing tumor necrosis, decreasing PCa proliferation and reducing local invasion and distal metastases. The ALT-100 mAb inhibits NFκB phosphorylation and signaling in PCa cells both in vitro and in vivo. This study demonstrates that eNAMPT neutralization effectively prevents human PCa aggressive progression in preclinical models, indicating its high potential to directly address the unmet need for an effective targeted therapy for patients with aggressive PCa.
• Sun, X., Sammani, S., Moreno-vinasco, L., Sun, B., Song, J. H., Mascarenhas, J. B., Liu, Z., Garcia, J. G., Cress, A. E., Bime, C., Valera, D. G., Sun, X., Sun, B., Song, J. H., Sammani, S., Quijada, H., Oita, R. C., Natarajan, V., Moreno-vinasco, L., , Mascarenhas, J. B., et al. (2021). Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody.. The European respiratory journal, 57(5), 2002536. doi:10.1183/13993003.02536-2020
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  The severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 pandemic has highlighted the serious unmet need for effective therapies that reduce acute respiratory distress syndrome (ARDS) mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor (TLR)4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target..Wild-type C57BL/6J or endothelial cell (EC)-cNAMPT -/- knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced ("one-hit") or a combined LPS/ventilator ("two-hit")-induced acute inflammatory lung injury model. A NAMPT-specific monoclonal antibody (mAb) imaging probe (99mTc-ProNamptor) was used to detect NAMPT expression in lung tissues. Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were used in vitro and in vivo..Immunohistochemical, biochemical and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both pre-clinical ARDS models. Intravenous delivery of either eNAMPT-neutralising pAb or mAb significantly attenuated inflammatory lung injury (haematoxylin and eosin staining, bronchoalveolar lavage (BAL) protein, BAL polymorphonuclear cells, plasma interleukin-6) in both pre-clinical models. In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption. In vivo studies in wild-type and EC-cNAMPT -/- mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both pre-clinical ARDS models..These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway. In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine.
• Sun, X., Sun, B. L., Sammani, S., Bermudez, T., Dudek, S. M., Camp, S. M., & Garcia, J. G. (2021). Genetic and epigenetic regulation of the non-muscle myosin light chain kinase isoform by lung inflammatory factors and mechanical stress. Clinical science (London, England : 1979), 135(7), 963-977.
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  The myosin light chain kinase gene, MYLK, encodes three proteins via unique promoters, including the non-muscle isoform of myosin light chain kinase (nmMLCK), a cytoskeletal protein centrally involved in regulation of vascular integrity. As MYLK coding SNPs are associated with severe inflammatory disorders (asthma, acute respiratory distress syndrome (ARDS)), we explored clinically relevant inflammatory stimuli and promoter SNPs in nmMLCK promoter regulation.
• Casanova, N. G., Gonzalez-Garay, M. L., Sun, B., Bime, C., Sun, X., Knox, K. S., Crouser, E. D., Sammani, N., Gonzales, T., Natt, B., Chaudhary, S., Lussier, Y., & Garcia, J. G. (2020). Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas. Respiratory research, 21(1), 321.
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  Despite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures.
• Garcia, J. G., Yuan, J., Desai, A., Wang, J., Camp, S., Moreno-Vinasco, L., Kempf, C., Sammani, S., Rischard, F., Gupta, G., Gupta, A., Tang, H., Casanova, N., Oita, R., Vanderpool, R., Babicheva, A., Sun, B., & Sun, X. (2020). Direct Extracellular NAMPT involvement in development of pulmonary hypertension: Transcriptional regulation by HIF2a. American Journal of Respiratory Cell and Molecular Biology.
• Quijada, H., Bermudez, T., Kempf, C. L., Valera, D. G., Garcia, A. N., Camp, S. M., Song, J. H., Franco, E., Burt, J. K., Sun, B., Mascarenhas, J. B., Burns, K., Gaber, A., Oita, R. C., Reyes Hernon, V., Barber, C., Moreno-Vinasco, L., Sun, X., Cress, A. E., , Martin, D., et al. (2020). Endothelial eNAMPT Amplifies Preclinical Acute Lung Injury: Efficacy of an eNAMPT-Neutralising mAb. The European respiratory journal.
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  The SARS-CoV-2/COVID-19 pandemic has highlighted the serious unmet need for effective therapies that reduce ARDS mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor 4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target.
• Sun, B. L., Sun, X., Casanova, N., Garcia, A. N., Oita, R., Algotar, A. M., Camp, S. M., Hernon, V. R., Gregory, T., Cress, A. E., & Garcia, J. G. (2020). Role of secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in prostate cancer progression: Novel biomarker and therapeutic target. EBioMedicine, 61, 103059.
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  There remains a serious need to prevent the progression of invasive prostate cancer (PCa). We previously showed that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator via TLR4 ligation which has been implicated in PCa progression. Here we investigate the role of eNAMPT as a diagnostic biomarker and therapeutic target in the progression of PCa.
• Sun, X., Sun, B. L., Babicheva, A., Vanderpool, R., Oita, R. C., Casanova, N., Tang, H., Gupta, A., Lynn, H., Gupta, G., Rischard, F., Sammani, S., Kempf, C. L., Moreno-Vinasco, L., Ahmed, M., Camp, S. M., Wang, J., Desai, A. A., Yuan, J. X., & Garcia, J. G. (2020). Direct eNAMPT Involvement in Pulmonary Hypertension and Vascular Remodeling: Transcriptional Regulation by SOX and HIF2α. American journal of respiratory cell and molecular biology.
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  We previously demonstrated involvement of nicotinamide phosphoribosyl-transferase in pulmonary arterial hypertension (PAH) and now examine NAMPT regulation and extracellular NAMPT's role in PAH vascular remodeling.
• Lynn, H., Sun, X., Casanova, N., Gonzales-Garay, M., Bime, C., & Garcia, J. G. (2019). Genomic and Genetic Approaches to Deciphering Acute Respiratory Distress Syndrome Risk and Mortality. Antioxidants & redox signaling, 31(14), 1027-1052.
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  Acute respiratory distress syndrome (ARDS) is a severe, highly heterogeneous critical illness with staggering mortality that is influenced by environmental factors, such as mechanical ventilation, and genetic factors. Significant unmet needs in ARDS are addressing the paucity of validated predictive biomarkers for ARDS risk and susceptibility that hamper the conduct of successful clinical trials in ARDS and the complete absence of novel disease-modifying therapeutic strategies. The current ARDS definition relies on clinical characteristics that fail to capture the diversity of disease pathology, severity, and mortality risk. We undertook a comprehensive survey of the available ARDS literature to identify genes and genetic variants (candidate gene and limited genome-wide association study approaches) implicated in susceptibility to developing ARDS in hopes of uncovering novel biomarkers for ARDS risk and mortality and potentially novel therapeutic targets in ARDS. We further attempted to address the well-known health disparities that exist in susceptibility to and mortality from ARDS. Bioinformatic analyses identified 201 ARDS candidate genes with pathway analysis indicating a strong predominance in key evolutionarily conserved inflammatory pathways, including reactive oxygen species, innate immunity-related inflammation, and endothelial vascular signaling pathways. Future studies employing a system biology approach that combines clinical characteristics, genomics, transcriptomics, and proteomics may allow for a better definition of biologically relevant pathways and genotype-phenotype connections and result in improved strategies for the sub-phenotyping of diverse ARDS patients molecular signatures. These efforts should facilitate the potential for successful clinical trials in ARDS and yield a better fundamental understanding of ARDS pathobiology.
• Liu, P., Rojo de la Vega, M., Sammani, S., Mascarenhas, J. B., Kerins, M., Dodson, M., Sun, X., Wang, T., Ooi, A., Garcia, J. G., & Zhang, D. D. (2018). RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE-dependent repression. Proceedings of the National Academy of Sciences of the United States of America, 115(44), E10352-E10361.
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  NRF2 regulates cellular redox homeostasis, metabolic balance, and proteostasis by forming a dimer with small musculoaponeurotic fibrosarcoma proteins (sMAFs) and binding to antioxidant response elements (AREs) to activate target gene transcription. In contrast, NRF2-ARE-dependent transcriptional repression is unreported. Here, we describe NRF2-mediated gene repression via a specific seven-nucleotide sequence flanking the ARE, which we term the NRF2-replication protein A1 (RPA1) element (NRE). Mechanistically, RPA1 competes with sMAF for NRF2 binding, followed by interaction of NRF2-RPA1 with the ARE-NRE and eduction of promoter activity. Genome-wide in silico and RNA-seq analyses revealed this NRF2-RPA1-ARE-NRE complex mediates negative regulation of many genes with diverse functions, indicating that this mechanism is a fundamental cellular process. Notably, repression of , which encodes the nonmuscle myosin light chain kinase, by the NRF2-RPA1-ARE-NRE complex disrupts vascular integrity in preclinical inflammatory lung injury models, illustrating the translational significance of NRF2-mediated transcriptional repression. Our findings reveal a gene-suppressive function of NRF2 and a subset of negatively regulated NRF2 target genes, underscoring the broad impact of NRF2 in physiological and pathological settings.
• Lynn, H. D., Sun, X., Ayshiev, D., Karnes, J. H., Gonzalez-Garay, M. L., Casanova, N., Wang, T., Garcia, J. G., & Siegler, J. H. (2018). Single nucleotide polymorphisms (SNPs) in the MYLKP1 pseudogene are associated with increased colon cancer risk in African Americans. PLOS ONE, 13, 13(8):e0200916.
• Mascarenhas, J. B., Sun, X., Wang, T., Sun, X., Mascarenhas, J. B., Kelly, G. T., Garcia, J. G., Dudek, S. M., Camp, S. M., & Brown, M. E. (2018). Myosin light chain kinase ( MYLK) coding polymorphisms modulate human lung endothelial cell barrier responses via altered tyrosine phosphorylation, spatial localization, and lamellipodial protrusions.. Pulmonary circulation, 8(2), 2045894018764171. doi:10.1177/2045894018764171
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  Sphingosine 1-phosphate (S1P) is a potent bioactive endogenous lipid that signals a rearrangement of the actin cytoskeleton via the regulation of non-muscle myosin light chain kinase isoform (nmMLCK). S1P induces critical nmMLCK Y464 and Y471 phosphorylation resulting in translocation of nmMLCK to the periphery where spatially-directed increases in myosin light chain (MLC) phosphorylation and tension result in lamellipodia protrusion, increased cell-cell adhesion, and enhanced vascular barrier integrity. MYLK, the gene encoding nmMLCK, is a known candidate gene in lung inflammatory diseases, with coding genetic variants (Pro21His, Ser147Pro, Val261Ala) that confer risk for inflammatory lung injury and influence disease severity. The functional mechanisms by which these MYLK coding single nucleotide polymorphisms (SNPs) affect biologic processes to increase disease risk and severity remain elusive. In the current study, we utilized quantifiable cell immunofluorescence assays to determine the influence of MYLK coding SNPs on S1P-mediated nmMLCK phosphorylation and translocation to the human lung endothelial cell (EC) periphery . These disease-associated MYLK variants result in reduced levels of S1P-induced Y464 phosphorylation, a key site for nmMLCK enzymatic regulation and activation. Reduced Y464 phosphorylation resulted in attenuated nmMLCK protein translocation to the cell periphery. We further conducted EC kymographic assays which confirmed that lamellipodial protrusion in response to S1P challenge was retarded by expression of a MYLK transgene harboring the three MYLK coding SNPs. These data suggest that ARDS/severe asthma-associated MYLK SNPs functionally influence vascular barrier-regulatory cytoskeletal responses via direct alterations in the levels of nmMLCK tyrosine phosphorylation, spatial localization, and lamellipodial protrusions.
• Sammani, S., Casanova, N., Zhou, T., Sun, X., Kittles, R. A., Karnes, J. H., Gonzalez-garay, M. L., Zhou, T., Yates, C. R., Wurfel, M. M., Wang, T., Sun, X., Sammani, S., Reilly, J. P., Pouladi, N., Meyer, N. J., Meduri, G. U., Lussier, Y. A., Kittles, R. A., , Kempf, C. L., et al. (2018). Genome-Wide Association Study in African Americans with Acute Respiratory Distress Syndrome Identifies the Selectin P Ligand Gene as a Risk Factor.. American journal of respiratory and critical care medicine, 197(11), 1421-1432. doi:10.1164/rccm.201705-0961oc
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  Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches..To identify genetic susceptibility targets for ARDS..A genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator-induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort..Pathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS-induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, Selplg-/- mice exhibited significantly reduced LPS-induced inflammatory lung injury compared with wild-type C57/B6 mice. Finally, an antibody that neutralizes P-selectin glycoprotein ligand 1 significantly attenuated LPS-induced lung inflammation..These findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.
• Sun, X., Wang, T., Sun, X., Singleton, P. A., Oita, R. C., Messana, J., Ma, W., Harbeck, M. C., Garcia, J. G., Ceco, E., & Camp, S. M. (2018). Novel Mechanism for Nicotinamide Phosphoribosyltransferase Inhibition of TNF-α-mediated Apoptosis in Human Lung Endothelial Cells.. American journal of respiratory cell and molecular biology, 59(1), 36-44. doi:10.1165/rcmb.2017-0155oc
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  Nicotinamide phosphoribosyltransferase (NAMPT) exists as both intracellular NAMPT and extracellular NAMPT (eNAMPT) proteins. eNAMPT is secreted into the blood and functions as a cytokine/enzyme (cytozyme) that activates NF-κB signaling via ligation of Toll-like receptor 4 (TLR4), further serving as a biomarker for inflammatory lung disorders such as acute respiratory distress syndrome. In contrast, intracellular NAMPT is involved in nicotinamide mononucleotide synthesis and has been implicated in the regulation of cellular apoptosis, although the exact mechanisms for this regulation are poorly understood. We examined the role of NAMPT in TNF-α-induced human lung endothelial cell (EC) apoptosis and demonstrated that reduced NAMPT expression (siRNA) increases EC susceptibility to TNF-α-induced apoptosis as reflected by PARP-1 cleavage and caspase-3 activation. In contrast, overexpression of NAMPT served to reduce degrees of TNF-α-induced EC apoptosis. Inhibition of nicotinamide mononucleotide synthesis by FK866 (a selective NAMPT enzymatic inhibitor) failed to alter TNF-α-induced human lung EC apoptosis, suggesting that NAMPT-dependent NAD+ generation is unlikely to be involved in regulation of TNF-α-induced EC apoptosis. We next confirmed that TNF-α-induced EC apoptosis is attributable to NAMPT secretion into the EC culture media and subsequent eNAMPT ligation of TLR4 on the EC membrane surface. Silencing of NAMPT expression, direct neutralization of secreted eNAMPT by an NAMPT-specific polyclonal antibody (preventing TLR4 ligation), or direct TLR4 antagonism all served to significantly increase EC susceptibility to TNF-α-induced EC apoptosis. Together, these studies provide novel insights into NAMPT contributions to lung inflammatory events and to novel mechanisms of EC apoptosis regulation.
• Sun, X., Mathew, B., Sammani, S., Jacobson, J. R., & Garcia, J. G. (2017). Simvastatin-induced sphingosine 1-phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells. Pulmonary circulation, 7(1), 117-125.
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  We have demonstrated that simvastatin and sphingosine 1-phosphate (S1P) both attenuate increased vascular permeability in preclinical models of acute respiratory distress syndrome. However, the underlying mechanisms remain unclear. As Krüppel-like factor 2 (KLF2) serves as a critical regulator for cellular stress response in endothelial cells (EC), we hypothesized that simvastatin enhances endothelial barrier function via increasing expression of the barrier-promoting S1P receptor, S1PR1, via a KLF2-dependent mechanism. S1PR1 luciferase reporter promoter activity in human lung artery EC (HPAEC) was tested after simvastatin (5 μM), and S1PR1 and KLF2 protein expression detected by immunoblotting. In vivo, transcription and expression of S1PR1 and KLF2 in mice lungs were detected by microarray profiling and immunoblotting after exposure to simvastatin (10 mg/kg). Endothelial barrier function was measured by trans-endothelial electrical resistance with the S1PR1 agonist FTY720-(S)-phosphonate. Both S1PR1 and KLF2 gene expression (mRNA, protein) were significantly increased by simvastatin in vitro and in vivo. S1PR1 promoter activity was significantly increased by simvastatin (P 
• Elangovan, V. R., Camp, S. M., Kelly, G. T., Desai, A. A., Adyshev, D., Sun, X., Black, S. M., Wang, T., & Garcia, J. G. (2016). Endotoxin- and mechanical stress-induced epigenetic changes in the regulation of the nicotinamide phosphoribosyltransferase promoter. Pulmonary circulation, 6(4), 539-544.
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  Mechanical ventilation, a lifesaving intervention for patients with acute respiratory distress syndrome (ARDS), also unfortunately contributes to excessive mechanical stress and impaired lung physiological and structural integrity. We have elsewhere established the pivotal role of increased nicotinamide phosphoribosyltransferase (NAMPT) transcription and secretion as well as its direct binding to the toll-like receptor 4 (TLR4) in the progression of this devastating syndrome; however, regulation of this critical gene in ventilator-induced lung injury (VILI) is not well characterized. On the basis of an emerging role for epigenetics in enrichment of VILI and CpG sites within the NAMPT promoter and 5'UTR, we hypothesized that NAMPT expression and downstream transcriptional events are influenced by epigenetic mechanisms. Concomitantly, excessive mechanical stress of human pulmonary artery endothelial cells or lipopolysaccharide (LPS) treatment led to both reduced DNA methylation levels in the NAMPT promoter and increased gene transcription. Histone deacetylase inhibition by trichostatin A or Sirt-1-silencing RNA attenuates LPS-induced NAMPT expression. Furthermore, recombinant NAMPT administration induced TLR4-dependent global H3K9 hypoacetylation. These studies suggest a complex epigenetic regulatory network of NAMPT in VILI and ARDS and open novel strategies for combating VILI and ARDS.
• Sun, X., Elangovan, V. R., Shimizu, Y., Ma, S. F., Wang, T., & Garcia, J. G. (2016). Genetic and Epigenetic Regulation of Myosin Light Chain Kinase by Inflammatory Lung Disease Associated Polymorphisms. Journal of Investigative Medicine.
• Sun, X., Garcia, J. G., Sun, X., Rizzo, A. N., Letsiou, E., Garcia, J. G., & Dudek, S. M. (2016). ID: 124: ABL FAMILY KINASES MEDIATE LUNG VASCULAR PERMEABILITY AND INFLAMMATION IN ACUTE LUNG INJURY. Journal of Investigative Medicine, 64(4), 965-965. doi:10.1136/jim-2016-000120.110
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  Rationale Acute respiratory distress syndrome (ARDS) is a life-threatening disease process in which overwhelming inflammation causes disruption of the pulmonary endothelial cell (EC) barrier, leading to leakage of fluid and inflammatory cells from the blood stream into the airspaces. Current research aims to identify agents that could both decrease inflammation and increase pulmonary vascular barrier integrity. Recently published work suggests that imatinib, an FDA-approved Abl family kinase inhibitor, may attenuate vascular leak and inflammation; however the mechanism underlying these effects is not completely understood. In the present study we explored the effects of LPS on the expression of the Abl family kinases, c-Abl and Arg, as well as the effects of Abl family kinases on LPS-induced vascular permeability and inflammation. Methods In silico analyses of the promoter regions of Abl1 (encodes c-Abl) and Abl2 (encodes Arg) were analyzed for potential responsive elements using the online programs Genomatix, TFsearch, and Jaspar. Cultured human pulmonary artery ECs were challenged with LPS (100 ng/mL, 24 hrs), harvested using RNeasy kit and reverse transcribed to cDNA. RT-PCR was performed to assess alterations in the expression of Abl1 and Abl2 after LPS challenge. In separate studies, siRNA was used to selectively silence either c-Abl or Arg and inter-endothelial gap formation was assessed by measuring FITC-dextran binding to a biotinylated avidin substrate. Complementary immunofluorescence studies were carried out to assess effects on adherens junction distributions. Western blotting was used to assess the effects of c-Abl and Arg silencing on NFkB phosphorylation. Results In silico analyses revealed that c-Abl contains two antioxidant responsive elements, whereas Arg contains two mechanical stress responsive elements. LPS treatment caused an increase in the mRNA expression of c-Abl (1.5 fold, p Conclusions The Abl family kinases c-Abl and Arg play complementary but distinct roles in mediating vascular permeability and inflammation following LPS challenge. The promoter of Abl1 (c-Abl) contains antioxidant response elements and LPS causes an increase in c-Abl expression. Additionally, LPS increases the mRNA expression of c-Abl, but not Arg. C-Abl contributes to LPS-induced NFκB signaling; whereas Arg contributes to inter-endothelial gap formation and adherens junction stability. Inhibition of both of these kinases may be of benefit in patients with ARDS.
• Sun, X., Garcia, J. G., Wang, T., Sun, X., Shimizu, Y., Ma, S., Garcia, J. G., & Elangovan, R. (2016). ID: 110: GENETIC AND EPIGENETIC REGULATION OF MYOSIN LIGHT CHAIN KINASE BY INFLAMMATORY LUNG DISEASE ASSOCIATED POLYMORPHISMS. Journal of Investigative Medicine, 64(4), 963-964. doi:10.1136/jim-2016-000120.107
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  Rationale Myosin light chain kinase (MLCK), a central cytoskeletal regulator encoded by MYLK gene, regulates muscle contraction, cell migration, endothelial cell–cell adhesion, and barrier function, thereby playing key pathophysiological roles in lung inflammatory diseases. We previously identified that MYLK single nucleotide polymorphisms (SNPs) as well as haplotypes are significantly associated with severe sepsis, acute lung injury and asthma in African Americans (AA) and European Americans (EA). Here we examined genetic and epigenetic regulation of the MYLK promoter as well as the effects of SNPs on MLCK expression and activity, thereby influencing cytoskeletal balance and cell integrity. Methods A series of nested deletions from the ∼2.5 kb putative promoter fragment were fused to luciferase reporter vectors, and transfected into human lung endothelium. We next evaluated the influence of ARDS and asthma associated SNPs on transcription factor (TF) binding and promoter activity. Exon SNP rs2700408 and intronic SNP rs11714297 were associated with ARDS in AA (GWAS) and EA (Gao et al, 2006), respectively. Rs57186134 has high LD with rs936170, one asthma associated SNP in AA (Gao et al, 2007). The DNA fragments containing SNPs were generated by site-directed mutagenesis. Transcription factor binding to the MYLK promoter was detected by protein-DNA electrophoretic mobility shift assay. Genetic regulation of MYLK and influences of disease-associated SNPs from previous studies were measured by luciferase promoter activity assays following challenge with inflammatory factors and mechanical stretch. Results Deletion construct luciferase reporter analysis revealed that the MYLK promoter for nmMLCK contains distal inhibitory and proximal enhancing regulatory regions. Human endothelial cell challenge with either 18% cyclic stretch, demethylation agents (5-Aza), or inflammatory factor TNFα and IL-4 significantly up-regulate MYLK promoter activities (p Conclusion These findings suggest that the MYLK gene is transcriptionally regulated by mechanical stress and inflammatory factors, and modulated by SNPs associated with lung inflammatory diseases. These functional insights further strengthen the concept that MYLKcontributes to inflammatory disease susceptibility and represents a molecular target in complex lung disorders.
• Adyshev, D., Sun, X., Zhang, W., Garcia, J. G., & Dudek, S. M. (2015). Regulation of Radixin Gene Expression in Pulmonary Endothelium by LPS and Cyclic Stretch. The FASEB Journal, 29.
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  Increased lung vascular permeability is a cardinal feature of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We previously have shown that the ezrin, radixin, and moesin (ERM) proteins differentially participate in agonists-induced endothelial cell (EC) barrier enhancement and hyperpermeability. In the present study we explore the regulation of radixin gene expression in lung inflammation by disease-associated genetic variants in the promoter and intronic regions of the RDX. A combination of genomic wide association study (GWAS), in silico analysis, and transfection of RDX promoter luciferase reporter were utilized. We analyzed RDX expression with Genomatix and Haploview for gene regulation and allele linkage disequilibrium (LD), respectively. Inflammatory stimuli LPS and 18% cyclic stretch (a model of mechanical lung injury) each time-dependently modulate both the protein expression of radixin and phosphorylation of ERMs. A GWAS study of African Americans identified one promoter (rs1...
• Shimizu, Y., Camp, S. M., Sun, X., Zhou, T., Wang, T., & Garcia, J. G. (2015). Sp1-mediated nonmuscle myosin light chain kinase expression and enhanced activity in vascular endothelial growth factor-induced vascular permeability. Pulmonary circulation, 5(4), 707-15.
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  Despite the important role played by the nonmuscle isoform of myosin light chain kinase (nmMLCK) in vascular barrier regulation and the implication of both nmMLCK and vascular endothelial growth factor (VEGF) in the pathogenesis of acute respiratory distress syndrome (ARDS), the role played by nmMLCK in VEGF-induced vascular permeability is poorly understood. In this study, the role played by nmMLCK in VEGF-induced vascular hyperpermeability was investigated. Human lung endothelial cell barrier integrity in response to VEGF is examined in both the absence and the presence of nmMLCK small interfering RNAs. Levels of nmMLCK messenger RNA (mRNA), protein, and promoter activity expression were monitored after VEGF stimulation in lung endothelial cells. nmMYLK promoter activity was assessed using nmMYLK promoter luciferase reporter constructs with a series of nested deletions. nmMYLK transcriptional regulation was further characterized by examination of a key transcriptional factor. nmMLCK plays an important role in VEGF-induced permeability. We found that activation of the VEGF signaling pathway in lung endothelial cells increases MYLK gene product at both mRNA and protein levels. Increased nmMLCK mRNA and protein expression is a result of increased nmMYLK promoter activity, regulated in part by binding of the Sp1 transcription factor on triggering by the VEGF signaling pathway. Taken together, these findings suggest that MYLK is an important ARDS candidate gene and a therapeutic target that is highly influenced by excessive VEGF concentrations in the inflamed lung.
• Adyshev, D. M., Elangovan, V. R., Moldobaeva, N., Mapes, B., Sun, X., & Garcia, J. G. (2014). Mechanical stress induces pre-B-cell colony-enhancing factor/NAMPT expression via epigenetic regulation by miR-374a and miR-568 in human lung endothelium. American journal of respiratory cell and molecular biology, 50(2), 409-18.
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  Increased lung vascular permeability and alveolar edema are cardinal features of inflammatory conditions such as acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). We previously demonstrated that pre-B-cell colony-enhancing factor (PBEF)/NAMPT, the proinflammatory cytokine encoded by NAMPT, participates in ARDS and VILI inflammatory syndromes. The present study evaluated posttranscriptional regulation of PBEF/NAMPT gene expression in human lung endothelium via 3'-untranslated region (UTR) microRNA (miRNA) binding. In silico analysis identified hsa-miR-374a and hsa-miR-568 as potential miRNA candidates. Increased PBEF/NAMPT transcription (by RT-PCR) and expression (by Western blotting) induced by 18% cyclic stretch (CS) (2 h: 3.4 ± 0.06 mRNA fold increase (FI); 10 h: 1.5 ± 0.06 protein FI) and by LPS (4 h: 3.8 ± 0.2 mRNA FI; 48 h: 2.6 ± 0.2 protein FI) were significantly attenuated by transfection with mimics of hsa-miR-374a or hsa-miR-568 (40-60% reductions each). LPS and 18% CS increased the activity of a PBEF/NAMPT 3'-UTR luciferase reporter (2.4-3.25 FI) with induction reduced by mimics of each miRNA (44-60% reduction). Specific miRNA inhibitors (antagomirs) for each PBEF/NAMPT miRNA significantly increased the endogenous PBEF/NAMPT mRNA (1.4-3.4 ± 0.1 FI) and protein levels (1.2-1.4 ± 0.1 FI) and 3'-UTR luciferase activity (1.4-1.7 ± 0.1 FI) compared with negative antagomir controls. Collectively, these data demonstrate that increased PBEF/NAMPT expression induced by bioactive agonists (i.e., excessive mechanical stress, LPS) involves epigenetic regulation with hsa-miR-374a and hsa-miR-568, representing novel therapeutic strategies to reduce inflammatory lung injury.
• Mitra, S., Wade, M. S., Sun, X., Moldobaeva, N., Flores, C., Ma, S. F., Zhang, W., Garcia, J. G., & Jacobson, J. R. (2014). GADD45a promoter regulation by a functional genetic variant associated with acute lung injury. PloS one, 9(6), e100169.
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  Growth arrest DNA damage inducible alpha (GADD45a) is a stress-induced gene we have shown to participate in the pathophysiology of ventilator-induced lung injury (VILI) via regulation of mechanical stress-induced Akt ubiquitination and phosphorylation. The regulation of GADD45a expression by mechanical stress and its relationship with acute lung injury (ALI) susceptibility and severity, however, remains unknown.
• Sun, X., Elangovan, V. R., Mapes, B., Camp, S. M., Sammani, S., Saadat, L., Ceco, E., Ma, S. F., Flores, C., MacDougall, M. S., Quijada, H., Liu, B., Kempf, C. L., Wang, T., Chiang, E. T., & Garcia, J. G. (2014). The NAMPT promoter is regulated by mechanical stress, signal transducer and activator of transcription 5, and acute respiratory distress syndrome-associated genetic variants. American journal of respiratory cell and molecular biology, 51(5), 660-7.
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  Increased nicotinamide phosphoribosyltransferase (NAMPT) transcription is mechanistically linked to ventilator-induced inflammatory lung injury (VILI), with VILI severity attenuated by reduced NAMPT bioavailability. The molecular mechanisms of NAMPT promoter regulation in response to excessive mechanical stress remain poorly understood. The objective of this study was to define the contribution of specific transcription factors, acute respiratory distress syndrome (ARDS)-associated single nucleotide polymorphisms (SNPs), and promoter demethylation to NAMPT transcriptional regulation in response to mechanical stress. In vivo NAMPT protein expression levels were examined in mice exposed to high tidal volume mechanical ventilation. In vitro NAMPT expression levels were examined in human pulmonary artery endothelial cells exposed to 5 or 18% cyclic stretch (CS), with NAMPT promoter activity assessed using NAMPT promoter luciferase reporter constructs with a series of nested deletions. In vitro NAMPT transcriptional regulation was further characterized by measuring luciferase activity, DNA demethylation, and chromatin immunoprecipitation. VILI-challenged mice exhibited significantly increased NAMPT expression in bronchoalveolar lavage leukocytes and in lung endothelium. A mechanical stress-inducible region (MSIR) was identified in the NAMPT promoter from -2,428 to -2,128 bp. This MSIR regulates NAMPT promoter activity, mRNA expression, and signal transducer and activator of transcription 5 (STAT5) binding, which is significantly increased by 18% CS. In addition, NAMPT promoter activity was increased by pharmacologic promoter demethylation and inhibited by STAT5 silencing. ARDS-associated NAMPT promoter SNPs rs59744560 (-948G/T) and rs7789066 (-2,422A/G) each significantly elevated NAMPT promoter activity in response to 18% CS in a STAT5-dependent manner. Our results show that NAMPT is a key novel ARDS therapeutic target and candidate gene with genetic/epigenetic transcriptional regulation in response to excessive mechanical stress.
• Liu, B., Sun, X., Suyeoka, G., Garcia, J. G., & Leiderman, Y. I. (2013). TGFβ signaling induces expression of Gadd45b in retinal ganglion cells. Investigative ophthalmology & visual science, 54(2), 1061-9.
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  Growth arrest and DNA damage protein 45b (Gadd45b) functions as an intrinsic neuroprotective molecule protecting retinal ganglion cells (RGCs) from injury. This study was performed to elucidate further the induction pathway of Gadd45b expression in RGCs.
• Sun, X., Ma, S. F., Wade, M. S., Acosta-Herrera, M., Villar, J., Pino-Yanes, M., Zhou, T., Liu, B., Belvitch, P., Moitra, J., Han, Y. J., Machado, R., Noth, I., Natarajan, V., Dudek, S. M., Jacobson, J. R., Flores, C., & Garcia, J. G. (2013). Functional promoter variants in sphingosine 1-phosphate receptor 3 associate with susceptibility to sepsis-associated acute respiratory distress syndrome. American journal of physiology. Lung cellular and molecular physiology, 305(7), L467-77.
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  The genetic mechanisms underlying the susceptibility to acute respiratory distress syndrome (ARDS) are poorly understood. We previously demonstrated that sphingosine 1-phosphate (S1P) and the S1P receptor S1PR3 are intimately involved in lung inflammatory responses and vascular barrier regulation. Furthermore, plasma S1PR3 protein levels were shown to serve as a biomarker of severity in critically ill ARDS patients. This study explores the contribution of single nucleotide polymorphisms (SNPs) of the S1PR3 gene to sepsis-associated ARDS. S1PR3 SNPs were identified by sequencing the entire gene and tagging SNPs selected for case-control association analysis in African- and ED samples from Chicago, with independent replication in a European case-control study of Spanish individuals. Electrophoretic mobility shift assays, luciferase activity assays, and protein immunoassays were utilized to assess the functionality of associated SNPs. A total of 80 variants, including 29 novel SNPs, were identified. Because of limited sample size, conclusive findings could not be drawn in African-descent ARDS subjects; however, significant associations were found for two promoter SNPs (rs7022797 -1899T/G; rs11137480 -1785G/C), across two ED samples supporting the association of alleles -1899G and -1785C with decreased risk for sepsis-associated ARDS. In addition, these alleles significantly reduced transcription factor binding to the S1PR3 promoter; reduced S1PR3 promoter activity, a response particularly striking after TNF-α challenge; and were associated with lower plasma S1PR3 protein levels in ARDS patients. These highly functional studies support S1PR3 as a novel ARDS candidate gene and a potential target for individualized therapy.
• Sun, X., Zhou, T., Zhou, T., Wang, T., Sun, X., Shimizu, Y., & Garcia, J. G. (2013). Abstract 18761: Non-Muscle Myosin Light Chain Kinase Mediates Vascular Endothelial Growth Factor Induced Vascular Hyperpermeability via Specificity Protein 1 During Asthmatic Inflammation. Circulation, 128.
• Sun, X., Singleton, P. A., Letsiou, E., Zhao, J., Belvitch, P., Sammani, S., Chiang, E. T., Moreno-Vinasco, L., Wade, M. S., Zhou, T., Liu, B., Parastatidis, I., Thomson, L., Ischiropoulos, H., Natarajan, V., Jacobson, J. R., Machado, R. F., Dudek, S. M., & Garcia, J. G. (2012). Sphingosine-1-phosphate receptor-3 is a novel biomarker in acute lung injury. American journal of respiratory cell and molecular biology, 47(5), 628-36.
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  The inflamed lung exhibits oxidative and nitrative modifications of multiple target proteins, potentially reflecting disease severity and progression. We identified sphingosine-1-phosphate receptor-3 (S1PR3), a critical signaling molecule mediating cell proliferation and vascular permeability, as a nitrated plasma protein in mice with acute lung injury (ALI). We explored S1PR3 as a potential biomarker in murine and human ALI. In vivo nitrated and total S1PR3 concentrations were determined by immunoprecipitation and microarray studies in mice, and by ELISA in human plasma. In vitro nitrated S1PR3 concentrations were evaluated in human lung vascular endothelial cells (ECs) or within microparticles shed from ECs after exposure to barrier-disrupting agonists (LPS, low-molecular-weight hyaluronan, and thrombin). The effects of S1PR3-containing microparticles on EC barrier function were assessed by transendothelial electrical resistance (TER). Nitrated S1PR3 was identified in the plasma of murine ALI and in humans with severe sepsis-induced ALI. Elevated total S1PR3 plasma concentrations (> 251 pg/ml) were linked to sepsis and ALI mortality. In vitro EC exposure to barrier-disrupting agents induced S1PR3 nitration and the shedding of S1PR3-containing microparticles, which significantly reduced TER, consistent with increased permeability. These changes were attenuated by reduced S1PR3 expression (small interfering RNAs). These results suggest that microparticles containing nitrated S1PR3 shed into the circulation during inflammatory lung states, and represent a novel ALI biomarker linked to disease severity and outcome.
• Sun, X., Tauler, J., Sun, X., Siegler, J., Moreno-vinasco, L., & Garcia, J. G. (2012). Abstract 352: hnRNP A2/B1 regulates S1PR3 expression in lung cancer. Cancer Research, 72, 352-352. doi:10.1158/1538-7445.am2012-352
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  Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Several clinical trials have shown that elevated expression of heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) in exfoliated bronchial epithelial cells correlates with eventual development of lung cancer. Cells with high levels of hnRNP A2/B1 expression have also been reported to manifest multiple molecular features of genetic injury. The hnRNPs are a complex group of RNA-binding proteins which play a key role in mRNA processing: stability, splicing, export and subcellular localization and participate also in telomere biogenesis. To elucidate the mechanism that links hnRNP A2/B1 overexpression with lung cancer progression we have knocked down hnRNPA2/B1 mRNA in non-small cell lung cancer (NSCLC) cell line A549 with a stable siRNA vector-based system. Silencing hnRNP A2/B1 increased proliferation and decreased migration in A549 and H1703 cell lines. These changes in migration and proliferation in A549 and H1703 hnRNPA2/B1-silenced cell lines correlated with an increase of E-Cadherin expression in both cell lines at mRNA and protein level. This increase in E-Cadherin expression was accompanied with a down-regulation of E-Cadherin inhibitors Twist1 and Snai1. We have proposed that hnRNP A2/B1 modulates epithelial-mesenchymal transition (EMT) in lung cancer cell lines that present a mesenchymal or intermediate phenotype such as H1703 and A549. It has been proposed that EMT may induce metastasis of cells with a mesenchymal phenotype. After metastatic seeding, EMT would be reversed trough mesenchymal-epithelial transition (MET) allowing tumor growth. However, mechanisms that regulate reversion of EMT are still poorly characterized. Interestingly, sphingosine 1-phospate (S1P) is an important angiogenic factor and regulator of vascular permeability. Microarray expression analysis revealed that silencing hnRNP A2/B1 decreases expression of the sphingosine 1-phosphate receptor 3 (S1PR3), a pro-migration RhoGTPAse activating S1P receptor, in A549 cells. Therefore, Moreover, S1P also stimulates motility of cancer cells through S1P receptors. It has been described that S1PR3 regulates migration and invasion in breast, prostate and gastric cancer. In A549 cells, S1PR3 is the most abundant receptor for S1P. Here we report that down regulation of hnRNP A2/B1, in lung cancer cells, decreases S1PR3 expression at the mRNA and protein level. We propose that further study of the mechanistic link between hnRNP A2/B1, S1P function and S1P receptors may allow a better understanding of the molecular mechanisms involved in invasion, metastasis. It may also provide new insights regarding the interaction between endothelial and epithelial cells and the regulation of EMT during tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 352. doi:1538-7445.AM2012-352
• Mathew, B., Jacobson, J. R., Berdyshev, E., Huang, Y., Sun, X., Zhao, Y., Gerhold, L. M., Siegler, J., Evenoski, C., Wang, T., Zhou, T., Zaidi, R., Moreno-Vinasco, L., Bittman, R., Chen, C. T., LaRiviere, P. J., Sammani, S., Lussier, Y. A., Dudek, S. M., , Natarajan, V., et al. (2011). Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 25(10), 3388-400.
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  Clinically significant radiation-induced lung injury (RILI) is a common toxicity in patients administered thoracic radiotherapy. Although the molecular etiology is poorly understood, we previously characterized a murine model of RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and genome-wide lung gene mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We hypothesized that sphingolipid signaling components serve as modulators and novel therapeutic targets of RILI. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to sphingosine 1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage fluid, and lung tissue. Mice with a targeted deletion of SphK1 (SphK1(-/-)) or with reduced expression of S1P receptors (S1PR1(+/-), S1PR2(-/-), and S1PR3(-/-)) exhibited marked RILI susceptibility. Finally, studies of 3 potent vascular barrier-protective S1P analogs, FTY720, (S)-FTY720-phosphonate (fTyS), and SEW-2871, identified significant RILI attenuation and radiation-induced gene dysregulation by the phosphonate analog, fTyS (0.1 and 1 mg/kg i.p., 2×/wk) and to a lesser degree by SEW-2871 (1 mg/kg i.p., 2×/wk), compared with those in controls. These results support the targeting of S1P signaling as a novel therapeutic strategy in RILI.
• Pino-Yanes, M., Ma, S. F., Sun, X., Tejera, P., Corrales, A., Blanco, J., Pérez-Méndez, L., Espinosa, E., Muriel, A., Blanch, L., Garcia, J. G., Villar, J., & Flores, C. (2011). Interleukin-1 receptor-associated kinase 3 gene associates with susceptibility to acute lung injury. American journal of respiratory cell and molecular biology, 45(4), 740-5.
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  Sepsis is the most common cause of acute lung injury (ALI), leading to organ dysfunction and death in critically ill patients. Previous studies associated variants of interleukin-1 receptor-associated kinase genes (IRAKs) with differential immune responses to pathogens and with outcomes during sepsis, and revealed that increased expression levels of the IRAK3 gene were correlated with poor outcomes during sepsis. Here we explored whether common variants of the IRAK3 gene were associated with susceptibility to, and outcomes of, severe sepsis. After our discovery of polymorphism, we genotyped a subset of seven single-nucleotide polymorphisms (SNPs) in 336 population-based control subjects and 214 patients with severe sepsis, collected as part of a prospective study of adults from a Spanish network of intensive care units. Whereas IRAK3 SNPs were not associated with susceptibility to severe sepsis, rs10506481 showed a significant association with the development of ALI among patients with sepsis (P = 0.007). The association remained significant after adjusting for multiple comparisons, population stratification, and clinical variables (odds ratio, 2.50; 95% confidence interval, 1.15-5.47; P = 0.021). By imputation, we revealed three additional SNPs independently associated with ALI (P < 0.01). One of these (rs1732887) predicted the disruption of a putative human-mouse conserved transcription factor binding site, and demonstrated functional effects in vitro (P = 0.017). Despite the need for replication in independent studies, our data suggest that common SNPs in the IRAK3 gene may be determinants of sepsis-induced ALI.
• Sammani, S., Moreno-Vinasco, L., Mirzapoiazova, T., Singleton, P. A., Chiang, E. T., Evenoski, C. L., Wang, T., Mathew, B., Husain, A., Moitra, J., Sun, X., Nunez, L., Jacobson, J. R., Dudek, S. M., Natarajan, V., & Garcia, J. G. (2010). Differential effects of sphingosine 1-phosphate receptors on airway and vascular barrier function in the murine lung. American journal of respiratory cell and molecular biology, 43(4), 394-402.
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  The therapeutic options for ameliorating the profound vascular permeability, alveolar flooding, and organ dysfunction that accompanies acute inflammatory lung injury (ALI) remain limited. Extending our previous finding that the intravenous administration of the sphingolipid angiogenic factor, sphingosine 1-phosphate (S1P), attenuates inflammatory lung injury and vascular permeability via ligation of S1PR(1), we determine that a direct intratracheal or intravenous administration of S1P, or a selective S1P receptor (S1PR(1)) agonist (SEW-2871), produces highly concentration-dependent barrier-regulatory responses in the murine lung. The intratracheal or intravenous administration of S1P or SEW-2871 at < 0.3 mg/kg was protective against LPS-induced murine lung inflammation and permeability. However, intratracheal delivery of S1P at 0.5 mg/kg (for 2 h) resulted in significant alveolar-capillary barrier disruption (with a 42% increase in bronchoalveolar lavage protein), and produced rapid lethality when delivered at 2 mg/kg. Despite the greater selectivity for S1PR(1), intratracheally delivered SEW-2871 at 0.5 mg/kg also resulted in significant alveolar-capillary barrier disruption, but was not lethal at 2 mg/kg. Consistent with the S1PR(1) regulation of alveolar/vascular barrier function, wild-type mice pretreated with the S1PR(1) inverse agonist, SB-649146, or S1PR(1)(+/-) mice exhibited reduced S1P/SEW-2871-mediated barrier protection after challenge with LPS. In contrast, S1PR(2)(-/-) knockout mice as well as mice with reduced S1PR(3) expression (via silencing S1PR3-containing nanocarriers) were protected against LPS-induced barrier disruption compared with control mice. These studies underscore the potential therapeutic effects of highly selective S1PR(1) receptor agonists in reducing inflammatory lung injury, and highlight the critical role of the S1P delivery route, S1PR(1) agonist concentration, and S1PR(1) expression in target tissues.
• Sun, X., Ma, S. F., Wade, M. S., Flores, C., Pino-Yanes, M., Moitra, J., Ober, C., Kittles, R., Husain, A. N., Ford, J. G., & Garcia, J. G. (2010). Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility. The Journal of allergy and clinical immunology, 126(2), 241-9, 249.e1-3.
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  The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma, and the sphingosine-1-phosphate receptor (S1PR1) is an essential participant regulating lung vascular integrity and responses to lung inflammation.
• Sun, X., Shikata, Y., Wang, L., Ohmori, K., Watanabe, N., Wada, J., Shikata, K., Birukov, K. G., Makino, H., Jacobson, J. R., Dudek, S. M., & Garcia, J. G. (2009). Enhanced interaction between focal adhesion and adherens junction proteins: involvement in sphingosine 1-phosphate-induced endothelial barrier enhancement. Microvascular research, 77(3), 304-13.
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  Sphingosine 1-phosphate (S1P) is an important vascular barrier regulatory agonist which enhances the junctional integrity of human lung endothelial cell monolayers. We have now demonstrated that S1P induced cortical actin ring formation and redistribution of focal adhesion kinase (FAK) and paxillin to the cell periphery suggesting the critical role of cell-cell adhesion in endothelial barrier enhancement. Co-immunoprecipitation studies revealed increased association of VE-cadherin with FAK and paxillin in S1P-challenged human pulmonary artery endothelial cell (HPAEC) monolayers. Furthermore, S1P-induced enhancement of VE-cadherin interaction with alpha-catenin and beta-catenin was associated with the increased formation of FAK-beta-catenin protein complexes. Depletion of beta-catenin (siRNA) resulted in loss of S1P-mediated VE-cadherin association with FAK and paxillin rearrangement. Furthermore, transendothelial electrical resistance (an index of barrier function) demonstrated that beta-catenin siRNA significantly attenuated S1P-induced barrier enhancement. These results demonstrate a mechanism of S1P-induced endothelial barrier enhancement via beta-catenin-linked adherens junction and focal adhesion interaction.
• Kamp, R., Sun, X., & Garcia, J. G. (2008). Making genomics functional: deciphering the genetics of acute lung injury. Proceedings of the American Thoracic Society, 5(3), 348-53.
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  Acute lung injury (ALI) is a common and frequently devastating illness characterized by acute hypoxemic respiratory failure, profound inflammation, and flooding of the alveoli. Despite recent advances in ALI care, the morbidity and mortality of ALI continues to be unacceptably high. ALI-inciting events (e.g., sepsis, trauma, aspiration, pneumonia) are quite common, yet only a fraction of patients develop the syndrome. This heterogeneity of patients presenting with ALI has sparked interest in identifying the role of genetic factors that contribute to ALI susceptibility and prognosis. Recent advances in high-throughput sequencing and expression technologies now provide the tools to perform large-scale genomic analyses in complex disorders such as ALI; gene expression profiling and pathway analysis provide further insight into previously described molecular pathways involved in the syndrome. In this article, we describe the use of genomewide association studies, ortholog in silico techniques, utility of consomic rat methods, and candidate gene approaches using expression profiling and pathway analyses. These methods have confirmed suspected ALI candidate genes (e.g., IL-6 and MIF), but more impressively have identified novel genes (e.g., GADD45alpha and PBEF) not previously suspected in ALI. The analysis of the molecular pathways (e.g., the cytoskeleton in vascular barrier regulation) has identified additional genes contributing to the development and severity of ALI (e.g., MLCK), thereby providing therapeutic targets in this devastating illness.

Proceedings Publications

• Sun, X., Karnes, J. H., Casanova, N. G., Sun, X., Lynn, H., Karnes, J. H., Garcia, J. G., Ellid, N., Coletta, D., Casanova, N. G., & Camp, S. M. (2020). Nicotinamide Phosphoribosyl Transferase (NAMPT) Genotype-Phenotype Haplotype and Elevated Extracellular NAMPT Levels Predict Mortality Outcomes in Acute Respiratory Distress Syndrome (ARDS). In C17. NOVEL APPROACHES TO ACUTE LUNG INJURY.
• Sun, X., Sun, X., Sun, B., Oita, R. C., Garcia, J. G., Gallegos, P., Cress, A. E., & Angle, D. (2020). Transcription Regulation of NAMPT by Radiation in Human Lung Endothelium and Epithelium. In C58. ACUTE LUNG INJURY: ATYPICAL TRIGGERS.
• Casanova, N. G., Gonzalez-garay, M. L., Sun, B., Sun, X., Sun, X., Sun, X., Sun, B., Gonzalez-garay, M. L., Garcia, J. G., & Casanova, N. G. (2019). Sarcoidosis and Coccidioidomycosis Share Common Tissue Transcriptome Expression Profiles. In B39. GRANULOMATOUS ILDs.
• Casanova, N. G., Sun, X., Sun, X., Lynn, H., Garcia, J. G., Ganay, M. G., Coletta, D., Casanova, N. G., & Bime, C. (2019). The mTOR Pathway Genes Are Differentially Methylated in African- and Hispanic- Americans Who Fail to Survive Acute Respiratory Distress Syndrome (ARDS). In C59. GENETIC AND EPIGENETIC MECHANISMS IN PULMONARY FIBROSIS.
• Sun, X., Sammani, S., Xie, L., Sun, X., Sammani, S., Moreno-vinasco, L., Letsiou, E., Jacobson, J. R., Garcia, J. G., & Dudek, S. M. (2012). Cyclic Stretch Induces Type 2 Deiodinase Expression In Lung Endothelial Cells. In C64. PULMONARY VASCULAR STRUCTURE, FUNCTION, AND SIGNALING.
• Sun, X., Sun, X., Mathew, B., Jacobson, J. R., Garcia, J. G., & Chen, W. (2012). Simvastatin Increases Human Sphingosine−1−Phosphate Receptor 1 Promoter Activity By Kruppel-Like Factor 2 In Human Lung Endothelium. In A67. ACUTE LUNG INJURY AND ACUTE RESPIRATORY DISTRESS SYNDROME: BIOLOGICAL MECHANISMS.
• Sun, X., Wade, M. S., Sun, X., Ma, S., Han, Y., & Garcia, J. G. (2012). A Promoter Polymorphism Of MYLK Associated With Asthma Upregulates Smooth Muscle Myosin Light Chain Kinase Isoform. In D31. ADVANCES IN ASTHMA GENETICS.
• Sun, X., Sammani, S., Zhao, J., Sun, X., Singleton, P. A., Sammani, S., Natarajan, V., Moreno-vinasco, L., Machado, R. F., Jacobson, J. R., Ischiropoulos, H., Garcia, J. G., Dudek, S. M., & Chiang, E. T. (2011). Nitrated Sphingosine 1-Phosphate Receptor 3 In Circulating Microparticles Is A Novel Biomarker For Acute Lung Injury. In B37. LUNG INJURY LESSONS AND BIOMARKERS FROM EXPOSURES TO TRANSPLANT.
• Sun, X., Wade, M. S., Sun, X., Moitra, J., Mapes, B. L., Machado, R. F., Ma, S., Garcia, J. G., Evenoski, C. L., Chiang, E. T., Al-saaka, M., & Adyshev, D. M. (2011). Functional Analysis Of Mechanical-Sensitive Elements In The Pbef Promoter: Influence Of Stat Family Transcription Factors. In B66. REGULATING GENE EXPRESSION: MI-RNA, GROWTH FACTORS, ETC..
• Sun, X., Zhou, T., Sammani, S., Zhou, T., Zhao, Y., Zaidi, R., Weichselbaum, R. R., Wang, T., Sun, X., Siegler, J., Sammani, S., Natarajan, V., Moreno-vinasco, L., Mathew, B., Lussier, Y. A., Lariviere, P. J., Jacobson, J. R., Huang, Y., Gerhold, L. M., , Garcia, J. G., et al. (2011). Critical Role Of Sphingolipid Pathway Components In Murine Radiation-Induced Lung Injury: Protection By Sphingosine 1 Phosphate Analogues. In A61. LUNG ENDOTHELIUM FUNCTIONS: THE BARRIER AND BEYOND.
• Sun, X., Wade, M. S., Sun, X., Moitra, J., Ma, S., Han, Y., & Garcia, J. G. (2010). Two Functional Promoter Variants Of Sphingosine-1-Phosphate Receptor 3 Gene Decrease Human Susceptibility To Severe Sepsis-Associated Acute Lung Injury. In B98. ACUTE LUNG INJURY: NEW DISCOVERIES AND PROMISES.
• Sun, X., Wade, M. S., Sun, X., Pino-yanes, M., Ober, C., Moitra, J., Ma, S., Hussain, A., Garcia, J. G., Ford, J. G., & Flores, C. (2010). Functional Variants Of Sphingosine-1-phosphate Receptor 1 Gene Associate With Asthma Susceptibility. In A32. ASTHMA GENETICS AND GENOMICS.
• Sun, X., Zaidi, S. R., Weichselbaum, R. R., Sun, X., Sakka, M. A., Moreno-vinasco, L., Mathew, B., Jacobson, J. R., Garcia, J. G., Evenoski, C., & Dudek, S. M. (2010). Involvement Of Acute Lung Injury Genes In Murine Radiation-induced Lung Injury (RILI). In B32. LUNG INJURY: PATHWAYS AND TARGETS.

Poster Presentations

• Sun, X. (2020, May). Transcription Regulation of NAMPT by Radiation in Human Lung Endothelium and Epithelium. American Thoracic Society International Conference. Philadelphia, PA: American Thoracic Society.
• Garcia, J. G., Sun, X., Sun, B., Gonzalez-Garay, M. L., Casanova, N., Garcia, J. G., Sun, X., Sun, B., Gonzalez-Garay, M. L., & Casanova, N. (2019, May). Sarcoidosis And Coccidioidomycosis Share Common Tissue Transcriptome Expression Profiles. ATS International Conference. Dallas: American Thoracic Society.
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  In this study we compared sarcoidosis gene expression profiles of lung and lymph node granulomas to tissues from patients with tuberculosis and coccidioidomycosis or Valley Fever (VF), a soil-dwelling fungi disease endemic in the southwest. We also aimed to compare sarcoidosis tissue gene expression to our previous gene signatures derived from peripheral blood mononuclear (PBMC). Incorporation of precise approaches like molecular biomarkers in the differential diagnosis will facilitate and expedite the diagnosis.

Others

• Song, S., Yamamura, A., Yamamura, H., Babicheva, A., Tang, H., Ayon, R., Mcdermott, K. M., Sun, X., Black, S., Makino, A., & Yuan, J. (2016, April). Hot, Heat and Stretch All Contribute to the Enhanced Ca2+ Signaling in Pulmonary Arterial Hypertension. The FASEB Journal.