Steven R Knoper

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Scholarly Contributions

Journals/Publications

• Knoper, S. (2022). Lung Spatial Profiling Reveals a T Cell Signature in COPD Patients with Fatal SARS-CoV-2 Infection. Cells.
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  People with pre-existing lung diseases such as chronic obstructive pulmonary disease (COPD) are more likely to get very sick from SARS-CoV-2 disease 2019 (COVID-19). Still, an interrogation of the immune response to COVID-19 infection, spatially throughout the lung structure, is lacking in patients with COPD. For this study, we characterized the immune microenvironment of the lung parenchyma, airways, and vessels of never- and ever-smokers with or without COPD, all of whom died of COVID-19, using spatial transcriptomic and proteomic profiling. The parenchyma, airways, and vessels of COPD patients, compared to control lungs had (1) significant enrichment for lung-resident CD45RO+ memory CD4+ T cells; (2) downregulation of genes associated with T cell antigen priming and memory T cell differentiation; and (3) higher expression of proteins associated with SARS-CoV-2 entry and primary receptor ubiquitously across the ROIs and in particular the lung parenchyma, despite similar SARS-CoV-2 structural gene expression levels. In conclusion, the lung parenchyma, airways, and vessels of COPD patients have increased T-lymphocytes with a blunted memory CD4 T cell response and a more invasive SARS-CoV-2 infection pattern and may underlie the higher death toll observed with COVID-19.
• Knoper, S. (2021). Paradoxical effects of cigarette smoke and COPD on SARS-CoV-2 infection and disease.. BMC pulmonary medicine.
• Tomchaney, M., Contoli, M., Mayo, J., Baraldo, S., Li, S., Cabel, C. R., Bull, D. A., Lick, S. D., Malo, J., Knoper, S., Kim, S. S., Tram, J., Rojas-Quintero, J., Kraft, M., Ledford, J., Tesfaigzi, Y., Martinez, F., Thorne, C. A., Kheradmand, F., , Campos, S. K., et al. (2021). Paradoxical effects of cigarette smoke and COPD on SARS-CoV-2 infection and disease. BMC Pulmonary Medicine.
• Knoper, S. (2017). How prostacyclin therapy improves right ventricular function in pulmonary arterial hypertension.. The European respiratory journal.
• Vanderpool, R. R., Desai, A. A., Knapp, S. M., Simon, M. A., Abidov, A., Yuan, J. X., Garcia, J. G., Hansen, L. M., Knoper, S. R., Naeije, R., & Rischard, F. P. (2017). How prostacyclin therapy improves right ventricular function in pulmonary arterial hypertension. The European respiratory journal, 50(2).
• Vanderpool, R. R., Waxman, A. B., Vanderpool, R., Simon, M. A., Rischard, M., Rischard, F., Knoper, S. R., Jenkins, I. C., Hansen, L., & Champion, H. C. (2014). Afterload reduction governs improvement in RV systolic function and ventriculo-arterial adaptation in patients with pulmonary arterial hypertension (PAH) undergoing rapid dose escalation of treprostinil. European Respiratory Journal, 44.
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  The mechanism of vasoactive therapy in PAH on ventriculo-arterial interaction is not well established. Thus, we prospectively investigated the effect of treprostinil (TRE) on pulmonary vascular elastance (Ea), right ventricular (RV) systolic (Ees) and diastolic (s) elastance in PAH patients. Methods and Results: Single-beat RV pressure-volume analysis was performed in 9 functional class IV PAH patients before and after inpatient dose escalation, and gradual outpatient dose increase of TRE. Data are presented as mean+SEM. TRE dose was 12.8+0.46 ng/kg/min at discharge and 44.2+4.34 ng/kg/min by 3 months (mo.). TRE was associated with a decrease in Ea (2.44+0.26 mmHg/ml baseline, 1.95+0.49 mmHg/ml discharge, and 1.38+0.28 mmHg/ml 3 mo. Ees was decreased slightly at discharge (1.62+0.35 mmHg/ml baseline vs. 1.49+0.3 mmHg/ml) and then reduced further by 3 mo. (0.85+0.18 mmHg/ml). s was high but unaffected by TRE. Although Ees decreased at 3 mo., there was 906+530 mmHg*ml stroke work reserve with exercise and a 139+45 M increase in 6 minute walk distance. Baseline β was related to Ea (R 2 =0.35) but not Ees (R 2 =0.01). RV end-diastolic volumes (RVEDV) however remained elevated (218+24.5 ml) at 3 mo. Conclusions: Treprostinil primarily exerts its effects by lowering RV afterload (Ea). This effect governs the improvement in RV systolic pump failure and contractile reserve. RV stiffness is related to afterload but unaffected by treprostinil. Thus, small improvements in RVEDV are likely related to a decrease in high baseline preload dependent (heterometric) autoregulation.
• Knoper, S. (2011). Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension.. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.
• Knoper, S. (2009). Tadalafil therapy for pulmonary arterial hypertension.. Circulation.
• Alpert, J. S., Knoper, S. R., Bavry, A. A., & Alpert, J. S. (2000). Segmental wall motion abnormalities in an individual with idiopathic pulmonary hemosiderosis.. Cardiology, 93(3), 201-4. doi:10.1159/000007027
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  Idiopathic pulmonary hemosiderosis (IPH) is a rare condition characterized by diffuse pulmonary hemorrhage of unknown etiology. Cardiac involvement in the form of myocarditis and right ventricular hypertrophy have been reported to occur in association with IPH, although findings on echocardiography have not been described. Herein is presented a case of an adult with IPH and echocardiographic abnormalities.
• Knoper, S. (2000). Segmental wall motion abnormalities in an individual with idiopathic pulmonary hemosiderosis.. Cardiology.
• Coggan, J. S., Purnyn, S. L., Knoper, S. R., & Kreulen, D. L. (1994). Muscarinic inhibition of two potassium currents in guinea-pig prevertebral neurons: differentiation by extracellular cesium. Neuroscience, 59(2), 349-61.
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  Muscarinic responses were studied in dissociated guinea-pig celiac ganglion neurons using the whole-cell voltage-clamp technique. Muscarine (0.025-1 mM; EC50 = 95 microM) administered to cells for 1.5 s evoked inward shifts in holding current in 53 of 74 cells. The amplitude of the inward current transients decreased with hyperpolarization and the null potential averaged -71 +/- 3.4 mV (n = 11). The currents that underlie the responses to muscarine were examined with hyperpolarizing voltage stepping protocols to -100 mV from a holding potential of -30 mV. Eighty-one per cent of cells displayed voltage-dependent current relaxations characteristic of the M-potassium current. Twenty per cent of responding cells displayed no M-current but only a voltage-independent current consistent with a leak current. In the latter type of cells, the muscarine-evoked inward currents reversed near EK and became outward at more hyperpolarized potentials. Analysis of steady state I-V relationships before and after bath application of muscarine showed that the two muscarine-sensitive potassium currents were distributed differently among three types of cells: (i) with M-current (18%); (ii) with leak current (18%); and (iii) with M-current and with leak current (64%). Cesium and barium were used to differentiate the M-current and the muscarine-sensitive leak current. Barium (2 mM) reduced the M-current and the leak potassium current, whereas cesium (2 mM) reduced the M-current but did not affect leak current. Thus, barium reduced the amplitude of muscarinic responses by 79% but cesium reduced them by only 14%. We conclude that muscarinic responses in guinea-pig celiac neurons are produced by suppression of two K+ currents: the M-current and a muscarine-sensitive leak current. These two currents are differentially susceptible to the potassium channel blockers barium and cesium.
• Knoper, S. (1994). Muscarinic inhibition of two potassium currents in guinea-pig prevertebral neurons: differentiation by extracellular cesium.. Neuroscience.
• Knoper, S. (1994). The muscarinic receptor agonist oxotremorine methiodide evokes a nicotinic response in mammalian sympathetic neurons.. European journal of pharmacology.
• Xian, H., Coggan, J. S., Knoper, S. R., & Kreulen, D. L. (1994). The muscarinic receptor agonist oxotremorine methiodide evokes a nicotinic response in mammalian sympathetic neurons. European journal of pharmacology, 259(1), 21-5.
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  Oxotremorine methiodide, a congener of oxotremorine, is used as a muscarinic receptor agonist. Responses to oxotremorine methiodide and nicotinic receptor agonists were examined in cultured guinea-pig celiac ganglion neurons using whole-cell voltage clamp techniques. At holding potentials between -30 and -60 mV, a brief application of oxotremorine methiodide produced fast and slow inward current transients, depending upon the concentration applied. Slowly developing inward current transients, characteristic of muscarinic responses, were produced by lower concentrations (EC50: 0.3 microM) and were blocked by atropine. Rapid inward current transients, characteristic of nicotinic responses, were produced by higher concentrations of oxotremorine methiodide (EC50: 168 microM) and were blocked by d-tubocurarine. Thus oxotremorine methiodide, at concentrations of 10 microM and greater, produced an initial nicotinic fast inward current transient followed by a slow muscarinic inward transient. The fast inward transients were similar to responses evoked by the nicotinic receptor agonists acetylcholine, nicotine and 1,1-dimethyl-4-phenyl-piperazinium iodide and were not antagonized by atropine. We conclude that oxotremorine methiodide acts as a nicotinic and muscarinic receptor agonist in celiac sympathetic ganglion neurons.
• Knoper, S. (1993). CCKA receptors mediate slow depolarizations in cultured mammalian sympathetic neurons.. European journal of pharmacology.
• Knoper, S. R., Meehan, A. G., Purnyn, S., Coggan, J. S., Anthony, T. L., & Kreulen, D. L. (1993). CCKA receptors mediate slow depolarizations in cultured mammalian sympathetic neurons. European journal of pharmacology, 232(1), 65-9.
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  The effect of cholecystokinin octapeptide (CCK-8) was examined in guinea-pig celiac ganglion (CG) neurons in primary culture using standard intracellular recording techniques. Sulfated CCK-8 (CCK-8S; 1 microM) evoked slow depolarizing responses in 94% of CG neurons tested. In contrast, membrane potential was not affected by nonsulfated CCK-8 (CCK-8NS; 1 microM), CCK tetrapeptide (CCK-4; 1 microM), or gastrin (1 microM). The selective CCKA receptor antagonist L 364,718 potently inhibited CCK-8S-induced slow depolarizations (IC50 2.9 pM). In contrast, the selective CCKB receptor antagonist L 365,260 was a weak inhibitor of CCK-8S-induced slow depolarizations (IC50 1.3 microM). The depolarizing responses to CCK-8S were associated with an average increase in cell input resistance of 61%. Single electrode voltage clamp experiments indicated that CCK-8S-induced depolarizations were associated with a slow inward shift in holding current. Thus, the present findings indicate that guinea-pig cultured CG neurons are endowed with excitatory CCKA receptors the activation of which elicits a decrease in membrane conductance, thereby resulting in slow depolarizations.
• Knoper, S. (1992). Response to 5-hydroxytryptamine on neurons of guinea pig celiac and inferior mesenteric ganglia in primary culture.. Life sciences.
• Knoper, S. R., Matsumoto, S. G., & Kreulen, D. L. (1992). Response to 5-hydroxytryptamine on neurons of guinea pig celiac and inferior mesenteric ganglia in primary culture. Life sciences, 51(9), 703-10.
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  The electrophysiological effects of serotonin, a putative neurotransmitter in prevertebral sympathetic ganglia, were evaluated in cultured celiac and inferior mesenteric ganglia (IMG) neurons. Intracellular microelectrode recordings were performed in neurons that were maintained in culture an average of 26 days. Seventy-eight of 85 neurons responded when serotonin (10 microM) was applied by pressure ejection from a micropipette to the surface of the isolated cells. The majority of the neurons (n = 48) generated fast depolarizations, although slow depolarizations (n = 17), bipolar responses (n = 5), hyperpolarizations (n = 7), and a biphasic response (n = 1), were also seen. Hyperpolarizing responses were evoked in celiac neurons only. All responses were inhibited by the 5-HT3 antagonist MDL 72,222 (5 microM). Fast responses were not inhibited by tetrodotoxin (n = 3). These results demonstrate that serotonin evokes a variety of membrane potential changes in cultured prevertebral sympathetic neurons by activating 5-HT3 receptors.
• Xian, H., Kreulen, D. L., Knoper, S. R., & Coggan, J. S. (1992). Activation of prevertebral sympathetic neurons by muscarinic and cholecystokinin receptors is mediated by different currents. Gastroenterology, 103(4), 1393. doi:10.1016/0016-5085(92)91621-a
• Matsumoto, S. M., Kreulen, D. L., Knoper, S. R., Coggan, J. S., & Anthony, T. L. (1991). Transmitter expression and pharmacologic responses of sympathetic neurones in primary culture. Journal of The Autonomic Nervous System, 33(2), 215-216. doi:10.1016/0165-1838(91)90220-w
• Knoper, S. (1988). Systemic fungal infections: diagnosis and treatment. I. Coccidioidomycosis.. Infectious disease clinics of North America.

Poster Presentations

• Bernardo, R., Vanderpool, R., Jenkins, I., Simon, M. A., Hansen, L., Champion, H. C., Knoper, S. R., & Rischard, F. (2015, January). A concentric hypertrophic right ventricular phenotype in advanced pulmonary arterial hypertension is associated with increased ventriculo-vascular stiffening and impaired treatment response to parenteral treprostinil. 8th Pulmonary Vascular Research Institute Annual World Congress. Guangzhou, China.
• Rischard, F., Vanderpool, R., Champion, H., Simon, M., Rischard, M., Jenkins, I., Knoper, S. R., Hansen, L., & Waxman, A. (2015, January). The prospective relationship of traditional metrics of RV function to right ventriculo-vascular coupling in patients with advanced pulmonary arterial hypertension undergoing titration of parenteral treprostinil. 8th Pulmonary Vascular Research Institute Annual World Congress. Guangzhou, China.
• Rischard, F., Vanderpool, R., Champion, H., Rischard, M., Jenkins, I., Knoper, S. R., & Waxman, A. (2014, September). Afterload Reduction Governs Improvement in RV Systolic Function and Ventriculo-Arterial Adaptation in Patients with Pulmonary Arterial Hypertension(PAH) Undergoing Rapid Dose Escalation of Tresprostinil. European Respiratory Society. Munich, Germany.
• Rischard, F., & Knoper, S. R. (2013, September). Surrogate Markers of Right Ventricular Adaptation Better Predict Long-term Survival in Patients with Pulmonary Arterial Hypertension On Therapy Than Traditional Prognostic Variables. European Respiratory Society Meeting. Barcelona, Spain.

Others

• Bernardo, R., Dalabih, M., Jenkins, I., Hansen, L., Knoper, S. R., & Rischard, F. (2015, Fall). Increased Afterload And Stroke Work During Exercise Does Not Amplify Resting Ventriculo-Vascular Uncoupling In Patients With Pulmonary Arterial Hypertension On Therapy. American Journal of Respiratory and Critical Care Medicine.
• Rischard, F., Bernardo, R., Vanderpool, R., Abidov, A., Jenkins, I., Simon, M. A., Hansen, L., Knoper, S. R., & Champion, H. C. (2015, Fall). 12. Right ventricular (RV) morphometric and ventriculo-vascular (VV) coupling patterns in patients with advanced pulmonary arterial hypertension (PAH) undergoing parenteral treprostinil therapy.
• Rischard, F., Jenkins, I., Raz, Y., Hansen, L., Thompson, J., Knoper, S. R., Hobson, N., & Hunter, K. S. (2015, Fall). RV Stroke Work Index Better Predicts Early Right Ventricular Uncoupling, Mortality, And Treatment Response Than Traditional Metrics Of Right Ventricular Function In Patients With Advanced Treatment Naive Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine.
• Hansen, L., Rischard, F., & Knoper, S. R. (2014, Fall). Right ventriculo-arterial coupling in patients with pulmonary arterial hypertension undergoing rapid dose escalation of treprostinil. Journal of Heart and Lung Transplantation.
• Knoper, S. R. (2014, April). Right ventriculo-arterial coupling in patients with pulmonary arterial hypertension undergoing rapid dose escalation of treprostinil. Journal of Heart and Lung Transplantation.
• Rischard, F., Champion, H. C., Vanderpool, R., Jenkins, I., Hansen, L., Knoper, S. R., & Waxman, A. (2014, May). Pulsatile unloading of the right ventricle results in significant afterload reduction in patients with pulmonary arterial hypertension undergoing rapid dose escalation of treprostinil. American Journal of Respiratory and Critical Care Medicine.
• Rischard, F., & Knoper, S. R. (2013, May). Surrogate Markers Of Right Ventricular Adaptation Better Predict Survival Than Does TAPSE In Patients With PAH Responding To Therapy. American Journal of Respiratory and Critical Care Medicine.
• Raz, Y., Daniel, J. C., Shah, H., Nolan, P. E., Knoper, S. R., & Moulton, M. J. (2012, September). A Three Month course of Pre-Operative Extracorporeal Membrane Oxygenation Culminating in pediatric Lung Transplantation. International Society for Heart and Lung Transplantation Annual Meeting.