ymjЯкутский медицинский журналYakut Medical Journal1813-19052312-1017ЯНЦ КМП10.1234/YMJ.2022.77.29ymj-170Research ArticleНАУЧНЫЕ ОБЗОРЫ И ЛЕКЦИИSCIENTIFIC REVIEWS AND LECTURESНарушение транспортной регуляции ионов и жидкости в легких при COVID-19Disruption of transport regulation of ions and fluid in the lungs with COVID-19СинякинИ. А.SinyakinI. A.

Синякин Иван Алексеевич – студент.

Ivan A. Sinyakin – student of the Amur State Medical Academy, 4th year, group 405, medical faculty.

sinyakin.ivan2016@yandex.ruБаталоваТ. А.BatalovaT. A.

Баталова Татьяна Анатольевна – д.б.н., доцент, зав. кафедрой.

Tatyana A. Batalova – Associate Professor, Doctor of Biological Sciences, Head of the department of Physiology and Pathophysiology of the Amur State Medical Academy.

batalova_ta@mail.ruФГБОУ ВО «Амурская ГМА»РоссияAmur State Medical AcademyRussian Federation20220502202501114117Copyright © Синякин И.А., Баталова Т.А., 20252025Синякин И.А., Баталова Т.А.Sinyakin I.A., Batalova T.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://ymj.elpub.ru/jour/article/view/170

В статье рассмотрены научные данные, основанные на современной литературе о нарушении транспорта ионов и жидкости в легких при COVID-19. Авторы исследования считают, что ингибирование TRPV4 (осмотически активируемого канала, связанного с ваниллоидным рецептором 4) имеет важное терапевтическое значение у пациентов с COVID-19, в частности мощные перспективы для защиты альвеолярно-капиллярного барьера и даже для регенерации поврежденного барьера. Клиническое испытание I фазы с использованием селективного ингибитора TRPV4 продемонстрировало благоприятный профиль безопасности у здоровых добровольцев группы контроля и у пациентов, страдающих кардиогенным отеком легких. Защита альвеолярно-капиллярного барьера селективным ингибитором TRPV4 также была бы полезна для устранения возможного легочного фиброза как позднего последствия COVID-19.

The article discusses scientific data on impaired transport of ions and fluids in the lungs with COVID-19. The authors of the study believe that inhibition of TRPV4 has important therapeutic benefits in COVID-19 patients in particular, powerful prospects for the protection of the alveolar-capillary barrier and even for the regeneration of a damaged barrier. A phase I of the clinical trial using a selective TRPV4 inhibitor demonstrated a favorable safety profile in healthy control volunteers and in patients with cardiogenic pulmonary edema. The protection of the alveolar-capillary barrier with a selective TRPV4 inhibitor would also be useful in eliminating possible pulmonary fibrosis as a late consequence of COVID-19.

COVID-19ENaCGPCRSARS-CoV-2TRPV4COVID-19ENaCGPCRSARS-CoV-2TRPV4ReferencesСинякин И.А. Обонятельная дисфункция как ключевой симптом COVID-19: обзор, основанный на современных исследованиях / И.А. Синякин, А.А. Панова, Т.А. Баталова // Якутский медицинский журнал. – 2021. – № 2(74). – С. 104-108. doi: 10.25789/YMJ.2021.74.27.Sinyakin I.A. Olfactory dysfunction as a key symptom of COVID-19: a review based on modern research / I. A. Sinyakin, A. A. Panova, T. A. Batalova. Yakut Medical Journal. - 2021. - No. 2 (74). - Рр. 104-108. - doi: 10.25789/YMJ.2021.74.27.Павленко В.И. Хроническая обструктивная болезнь легких как коморбидное состояние при Covid-19 / В.И. Павленко, Е.Г. Кулик, С.В. Нарышкина // Амурский медицинский журнал. - 2021. - N1. - С. 11–17. doi:10.24412/2311-5068-2021-1-11-17.Pavlenko V.I., Kulik E.G., Naryshkina S.V. Chronic obstructive pulmonary disease as a comorbid state in Covid-19. Amur Medical Journal, 2021; No 1, pp.11–17. doi:10.24412/2311-5068-2021-1-11-17.Abdel Hameid R, Cormet-Boyaka E, Kuebler WM, Uddin M, Berdiev BK. SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport. Am J Physiol Lung Cell Mol Physiol 320: L430–L435, 2021. doi:10.1152/ajplung.00499.2020.Abdel Hameid R, Cormet-Boyaka E, Kuebler WM, Uddin M, Berdiev BK. SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport. Am J Physiol Lung Cell Mol Physiol 320: L430–L435, 2021. doi:10.1152/ajplung.00499.2020.Bharat A, Querrey M, Markov NS, Kim S, Kurihara C, Garza-Castillon R, Manerikar A, Shilatifard A, Tomic R, Politanska Y, Abdala-Valencia H, Yeldandi AV, Lomasney JW, Misharin AV, Budinger GRS. Lung transplantation for patients with severe COVID-19. Sci Transl Med 12: eabe4282, 2020. doi:10.1126/scitranslmed.abe4282.Bharat A, Querrey M, Markov NS, Kim S, Kurihara C, Garza-Castillon R, Manerikar A, Shilatifard A, Tomic R, Politanska Y, Abdala-Valencia H, Yeldandi AV, Lomasney JW, Misharin AV, Budinger GRS. Lung transplantation for patients with severe COVID-19. Sci Transl Med 12: eabe4282, 2020. doi:10.1126/scitranslmed.abe4282.Brazee PL, Morales-Nebreda L, Magnani ND, Garcia JG, Misharin AV, Ridge KM, Budinger GRS, Iwai K, Dada LA, Sznajder JI. Linear ubiquitin assembly complex regulates lung epithelial-driven responses during influenza infection. J Clin Invest 130: 1301–1314, 2020. doi:10.1172/JCI128368.Brazee PL, Morales-Nebreda L, Magnani ND, Garcia JG, Misharin AV, Ridge KM, Budinger GRS, Iwai K, Dada LA, Sznajder JI. Linear ubiquitin assembly complex regulates lung epithelial-driven responses during influenza infection. J Clin Invest 130: 1301–1314, 2020. doi:10.1172/JCI128368.Brazee PL, Soni PN, Tokhtaeva E, Magnani N, Yemelyanov A, Perlman HR, Ridge KM, Sznajder JI, Vagin O, Dada LA. FXYD5 Is an essential mediator of the inflammatory response during. Front Immunol 8: 623, 2017. doi:10.3389/fimmu.2017.00623.Brazee PL, Soni PN, Tokhtaeva E, Magnani N, Yemelyanov A, Perlman HR, Ridge KM, Sznajder JI, Vagin O, Dada LA. FXYD5 Is an essential mediator of the inflammatory response during. Front Immunol 8: 623, 2017. doi:10.3389/fimmu.2017.00623.Barrett KE. Rethinking cholera pathogenesis- no longer all in the same “camp”. Virulence 7: 751–753, 2016. doi:10.1080/21505594.2016.1212156.Barrett KE. Rethinking cholera pathogenesis- no longer all in the same “camp”. Virulence 7: 751–753, 2016. doi:10.1080/21505594.2016.1212156.Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, Jordan TX, Oishi K, Panis M, Sachs D, Wang TT, Schwartz RE, Lim JK, Albrecht RA, tenOever BR. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 181: 1036–1045.e9, 2020. doi:10.1016/j.cell.2020.04.026.Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, Jordan TX, Oishi K, Panis M, Sachs D, Wang TT, Schwartz RE, Lim JK, Albrecht RA, tenOever BR. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 181: 1036–1045.e9, 2020. doi:10.1016/j.cell.2020.04.026.Bojkova D, Klann K, Koch B, Widera M, Krause D, Ciesek S, Cinatl J, Münch C. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature 583: 469–472, 2020. doi:10.1038/s41586-020-2332-7.Bojkova D, Klann K, Koch B, Widera M, Krause D, Ciesek S, Cinatl J, Münch C. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature 583: 469–472, 2020. doi:10.1038/s41586-020-2332-7.Banerjee AK, Blanco MR, Bruce EA, Honson DD, Chen LM, Chow A, Bhat P, Ollikainen N, Quinodoz SA, Loney C, Thai J, Miller ZD, Lin AE, Schmidt MM, Stewart DG, Goldfarb D, De Lorenzo G, Rihn SJ, Voorhees RM, Botten JW, Majumdar D, Guttman M. SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses. Cell 183: 1325–1339.e21, 2020. doi:10.1016/j.cell.2020.10.004.Banerjee AK, Blanco MR, Bruce EA, Honson DD, Chen LM, Chow A, Bhat P, Ollikainen N, Quinodoz SA, Loney C, Thai J, Miller ZD, Lin AE, Schmidt MM, Stewart DG, Goldfarb D, De Lorenzo G, Rihn SJ, Voorhees RM, Botten JW, Majumdar D, Guttman M. SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses. Cell 183: 1325–1339.e21, 2020. doi:10.1016/j.cell.2020.10.004.Barquin N, Ciccolella DE, Ridge KM, Sznajder JI. Dexamethasone upregulates the Na-K-ATPase in rat alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 273: L825–L830, 1997. doi:10.1152/ajplung.1997.273.4.L825.Barquin N, Ciccolella DE, Ridge KM, Sznajder JI. Dexamethasone upregulates the Na-K-ATPase in rat alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 273: L825–L830, 1997. doi:10.1152/ajplung.1997.273.4.L825.Chen F, Zhang Y, Sucgang R, Ramani S, Corry D, Kheradmand F, Creighton CJ. Meta-analysis of host transcriptional responses to SARS-CoV-2 infection reveals their manifestation in human tumors. Sci Rep 11: 2459, 2021. doi:10.1038/s41598-021-82221-4.Chen F, Zhang Y, Sucgang R, Ramani S, Corry D, Kheradmand F, Creighton CJ. Meta-analysis of host transcriptional responses to SARS-CoV-2 infection reveals their manifestation in human tumors. Sci Rep 11: 2459, 2021. doi:10.1038/s41598-021-82221-4.Dada LA, Chandel NS, Ridge KM, Pedemonte C, Bertorello AM, Sznajder JI. Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-zeta. J Clin Invest 111: 1057–1064, 2003. doi:10.1172/JCI16826.Dada LA, Chandel NS, Ridge KM, Pedemonte C, Bertorello AM, Sznajder JI. Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-zeta. J Clin Invest 111: 1057–1064, 2003. doi:10.1172/JCI16826.Dagenais A, Fréchette R, Clermont ME, Massé C, Privé A, Brochiero E, Berthiaume Y. Dexamethasone inhibits the action of TNF on ENaC expression and activity. Am J Physiol Lung Cell Mol Physiol 291: L1220–L1231, 2006. doi:10.1152/ajplung.00511.2005.Dagenais A, Fréchette R, Clermont ME, Massé C, Privé A, Brochiero E, Berthiaume Y. Dexamethasone inhibits the action of TNF on ENaC expression and activity. Am J Physiol Lung Cell Mol Physiol 291: L1220–L1231, 2006. doi:10.1152/ajplung.00511.2005.Dutta B, Arya RK, Goswami R, Alharbi MO, Sharma S, Rahaman SO. Role of macrophage TRPV4 in inflammation. Lab Invest 100: 178-185, 2020. doi:10.1038/s41374-019-0334-6.Dutta B, Arya RK, Goswami R, Alharbi MO, Sharma S, Rahaman SO. Role of macrophage TRPV4 in inflammation. Lab Invest 100: 178-185, 2020. doi:10.1038/s41374-019-0334-6.Grant RA, Morales-Nebreda L, Markov NS, Swaminathan S, Querrey M, Guzman ER; The NU SCRIPT Study Investigators, et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature 590: 635–641, 2021. doi:10.1038/s41586-020-03148-w.Grant RA, Morales-Nebreda L, Markov NS, Swaminathan S, Querrey M, Guzman ER; The NU SCRIPT Study Investigators, et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature 590: 635–641, 2021. doi:10.1038/s41586-020-03148-w.Grove LM, Mohan ML, Abraham S, Scheraga RG, Southern BD, Crish JF, Naga Prasad SV, Olman MA. Translocation of TRPV4-PI3Kγ complexes to the plasma membrane drives myofibroblast transdifferentiation. Sci Signal 12: eaau1533, 2019. doi:10.1126/scisignal.aau1533.Grove LM, Mohan ML, Abraham S, Scheraga RG, Southern BD, Crish JF, Naga Prasad SV, Olman MA. Translocation of TRPV4-PI3Kγ complexes to the plasma membrane drives myofibroblast transdifferentiation. Sci Signal 12: eaau1533, 2019. doi:10.1126/scisignal.aau1533.Herrero R, Sanchez G, Lorente JA. New insights into the mechanisms of pulmonary edema in acute lung injury. Ann Transl Med 6: 32–32, 2018. doi:10.21037/atm.2017.12.18.Herrero R, Sanchez G, Lorente JA. New insights into the mechanisms of pulmonary edema in acute lung injury. Ann Transl Med 6: 32–32, 2018. doi:10.21037/atm.2017.12.18.Jha PK, Vijay A, Halu A, Uchida S, Aikawa M. Gene expression profiling reveals the shared and distinct transcriptional signatures in human lung epithelial cells infected with SARS-CoV-2, MERS-CoV, or SARS-CoV: potential implications in cardiovascular complications of COVID-19. Front Cardiovasc Med 7: 623012, 2021. doi:10.3389/fcvm.2020.623012.Jha PK, Vijay A, Halu A, Uchida S, Aikawa M. Gene expression profiling reveals the shared and distinct transcriptional signatures in human lung epithelial cells infected with SARS-CoV-2, MERS-CoV, or SARS-CoV: potential implications in cardiovascular complications of COVID-19. Front Cardiovasc Med 7: 623012, 2021. doi:10.3389/fcvm.2020.623012.Johnson RM, Vinetz JM. Dexamethasone in the management of COVID-19. BMJ 370: m2648, 2020. doi:10.1136/bmj.m2648.Johnson RM, Vinetz JM. Dexamethasone in the management of COVID-19. BMJ 370: m2648, 2020. doi:10.1136/bmj.m2648.Kryvenko V, Vadász I. Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19. Am J Physiol Lung Cell Mol Physiol. In press. doi:10.1152/ajplung.00056.2021.Kryvenko V, Vadász I. Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19. Am J Physiol Lung Cell Mol Physiol. In press. doi:10.1152/ajplung.00056.2021.Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA 97: 10430–10435, 2000. doi:10.1073/pnas.190332597.Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA 97: 10430–10435, 2000. doi:10.1073/pnas.190332597.Kuebler WM, Jordt SE, Liedtke WB. Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach. Am J Physiol Lung Cell Mol Physiol. 2020;318(6):L1239-L1243. doi:10.1152/ajplung.00161.2020Kuebler WM, Jordt SE, Liedtke WB. Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach. Am J Physiol Lung Cell Mol Physiol. 2020;318(6):L1239-L1243. doi:10.1152/ajplung.00161.2020Lazrak A, Iles KE, Liu G, Noah DL, Noah JW, Matalon S. Influenza virus M2 protein inhibits epithelial sodium channels by increasing reactive oxygen species. FASEB J 23: 3829–3842, 2009. doi:10.1096/fj.09-135590.Lazrak A, Iles KE, Liu G, Noah DL, Noah JW, Matalon S. Influenza virus M2 protein inhibits epithelial sodium channels by increasing reactive oxygen species. FASEB J 23: 3829–3842, 2009. doi:10.1096/fj.09-135590.Lobo MJ, Amaral MD, Zaccolo M, Farinha CM. EPAC1 activation by cAMP stabilizes CFTR at the membrane by promoting its interaction with NHERF1. J Cell Sci 129: 2599–2612, 2016. doi:10.1242/jcs.185629.Lobo MJ, Amaral MD, Zaccolo M, Farinha CM. EPAC1 activation by cAMP stabilizes CFTR at the membrane by promoting its interaction with NHERF1. J Cell Sci 129: 2599–2612, 2016. doi:10.1242/jcs.185629.Mangalmurti NS, Reilly JP, Cines DB, Meyer NJ, Hunter CA, Vaughan AE. COVID-19– associated acute respiratory distress syndrome clarified: a vascular endotype? Am J Respir Crit Care Med 202: 750-753, 2020. doi:10.1164/rccm.202006-2598LE.Mangalmurti NS, Reilly JP, Cines DB, Meyer NJ, Hunter CA, Vaughan AE. COVID-19– associated acute respiratory distress syndrome clarified: a vascular endotype? Am J Respir Crit Care Med 202: 750-753, 2020. doi:10.1164/rccm.202006-2598LE.Mangalmurti N, Hunter CA. Cytokine storms: understanding COVID. Immunity 53: 19–25, 2020. doi:10.1016/j.immuni.2020.06.017.Mangalmurti N, Hunter CA. Cytokine storms: understanding COVID. Immunity 53: 19–25, 2020. doi:10.1016/j.immuni.2020.06.017.Mutlu GM, Adir Y, Jameel M, Akhmedov AT, Welch L, Dumasius V, Meng FJ, Zabner J, Koenig C, Lewis ER, Balagani R, Traver G, Sznajder JI, Factor P. Interdependency of beta-adrenergic receptors and CFTR in regulation of alveolar active Na+ transport. Circ Res 96: 999–1005, 2005. doi:10.1161/01.RES.0000164554.21993.AC.Mutlu GM, Adir Y, Jameel M, Akhmedov AT, Welch L, Dumasius V, Meng FJ, Zabner J, Koenig C, Lewis ER, Balagani R, Traver G, Sznajder JI, Factor P. Interdependency of beta-adrenergic receptors and CFTR in regulation of alveolar active Na+ transport. Circ Res 96: 999–1005, 2005. doi:10.1161/01.RES.0000164554.21993.AC.Matalon S, Bartoszewski R, Collawn JF. Role of epithelial sodium channels in the regulation of lung fluid homeostasis. Am J Physiol Lung Cell Mol Physiol 309: L1229–L1238, 2015. doi:10.1152/ajplung.00319.2015.Matalon S, Bartoszewski R, Collawn JF. Role of epithelial sodium channels in the regulation of lung fluid homeostasis. Am J Physiol Lung Cell Mol Physiol 309: L1229–L1238, 2015. doi:10.1152/ajplung.00319.2015.Monterisi S, Casavola V, Zaccolo M. Local modulation of cystic fibrosis conductance regulator: cytoskeleton and compartmentalized cAMP signalling. Br J Pharmacol 169: 1–9, 2013. doi:10.1111/bph.12017.Monterisi S, Casavola V, Zaccolo M. Local modulation of cystic fibrosis conductance regulator: cytoskeleton and compartmentalized cAMP signalling. Br J Pharmacol 169: 1–9, 2013. doi:10.1111/bph.12017.Olbei M, Hautefort I, Modos D, Treveil A, Poletti M, Gul L, Shannon-Lowe CD, Korcsmaros T. SARS-CoV-2 causes a different cytokine response compared to other cytokine storm-causing respiratory viruses in severely ill patients. Front Immunol 12: 629193, 2021. doi:10.3389/fimmu.2021.629193.Olbei M, Hautefort I, Modos D, Treveil A, Poletti M, Gul L, Shannon-Lowe CD, Korcsmaros T. SARS-CoV-2 causes a different cytokine response compared to other cytokine storm-causing respiratory viruses in severely ill patients. Front Immunol 12: 629193, 2021. doi:10.3389/fimmu.2021.629193.Peteranderl C, Sznajder JI, Herold S, Lecuona E. Inflammatory responses regulating alveolar ion transport during pulmonary infections. Front Immunol 8: 446, 2017. doi:10.3389/fimmu.2017.00446.Peteranderl C, Sznajder JI, Herold S, Lecuona E. Inflammatory responses regulating alveolar ion transport during pulmonary infections. Front Immunol 8: 446, 2017. doi:10.3389/fimmu.2017.00446.Peteranderl C, Morales-Nebreda L, Selvakumar B, Lecuona E, Vadasz I, Morty RE, Schmoldt C, Bespalowa J, Wolff T, Pleschka S, Mayer K, Gattenloehner S, Fink L, Lohmeyer J, Seeger W, Sznajder JI, Mutlu GM, Budinger GR, Herold S. Macrophage-epithelial paracrine cross-talk inhibits lung edema clearance during influenza infection. J Clin Invest 126: 1566–1580, 2016. doi:10.1172/JCI83931.Peteranderl C, Morales-Nebreda L, Selvakumar B, Lecuona E, Vadasz I, Morty RE, Schmoldt C, Bespalowa J, Wolff T, Pleschka S, Mayer K, Gattenloehner S, Fink L, Lohmeyer J, Seeger W, Sznajder JI, Mutlu GM, Budinger GR, Herold S. Macrophage-epithelial paracrine cross-talk inhibits lung edema clearance during influenza infection. J Clin Invest 126: 1566–1580, 2016. doi:10.1172/JCI83931.Prota LFM, Cebotaru L, Cheng J, Wright J, Vij N, Morales MM, Guggino WB. Dexamethasone regulates CFTR expression in Calu-3 cells with the involvement of chaperones HSP70 and HSP90. PLoS One 7: e47405, 2012. doi:10.1371/journal.pone.0047405.Prota LFM, Cebotaru L, Cheng J, Wright J, Vij N, Morales MM, Guggino WB. Dexamethasone regulates CFTR expression in Calu-3 cells with the involvement of chaperones HSP70 and HSP90. PLoS One 7: e47405, 2012. doi:10.1371/journal.pone.0047405.Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP; The Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 323: 2052-2059, 2020. [Erratum in JAMA 323: 2098, 2020]. doi:10.1001/jama.2020.6775.Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP; The Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 323: 2052-2059, 2020. [Erratum in JAMA 323: 2098, 2020]. doi:10.1001/jama.2020.6775.Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 39: 2085–2094, 2020. doi:10.1007/s10067-020-05190-5Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 39: 2085–2094, 2020. doi:10.1007/s10067-020-05190-5Stutts MJ, Canessa CM, Olsen JC, Hamrick M, Cohn JA, Rossier BC, Boucher RC. CFTR as a cAMP-dependent regulator of sodium channels. Science 269: 847–850, 1995. doi:10.1126/science.7543698.Stutts MJ, Canessa CM, Olsen JC, Hamrick M, Cohn JA, Rossier BC, Boucher RC. CFTR as a cAMP-dependent regulator of sodium channels. Science 269: 847–850, 1995. doi:10.1126/science.7543698.Siu KL, Chan CP, Kok KH, Woo PC, Jin DY. Comparative analysis of the activation of unfolded protein response by spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus HKU1. Cell Biosci 4: 3, 2014. doi:10.1186/2045-3701-4-3.Siu KL, Chan CP, Kok KH, Woo PC, Jin DY. Comparative analysis of the activation of unfolded protein response by spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus HKU1. Cell Biosci 4: 3, 2014. doi:10.1186/2045-3701-4-3.Song P, Li W, Xie J, Hou Y, You C. Cytokine storm induced by SARS-CoV-2. Clin Chim Acta 509: 280–287, 2020. doi:10.1016/j.cca.2020.06.017.Song P, Li W, Xie J, Hou Y, You C. Cytokine storm induced by SARS-CoV-2. Clin Chim Acta 509: 280–287, 2020. doi:10.1016/j.cca.2020.06.017.Short KR, Kroeze EJ, Fouchier RA, Kuiken T. Pathogenesis of influenza-induced acute respiratory distress syndrome. Lancet Infect Dis 14: 57–69, 2014. doi:10.1016/S1473-3099(13)70286-X.Short KR, Kroeze EJ, Fouchier RA, Kuiken T. Pathogenesis of influenza-induced acute respiratory distress syndrome. Lancet Infect Dis 14: 57–69, 2014. doi:10.1016/S1473-3099(13)70286-X.Tao X, Mei F, Agrawal A, Peters CJ, Ksiazek TG, Cheng X, Tseng CT. Blocking of exchange proteins directly activated by cAMP leads to reduced replication of Middle East respiratory syndrome coronavirus. J Virol 88: 3902–3910, 2014. doi:10.1128/JVI.03001-13.Tao X, Mei F, Agrawal A, Peters CJ, Ksiazek TG, Cheng X, Tseng CT. Blocking of exchange proteins directly activated by cAMP leads to reduced replication of Middle East respiratory syndrome coronavirus. J Virol 88: 3902–3910, 2014. doi:10.1128/JVI.03001-13.Tokhtaeva E, Sun H, Deiss-Yehiely N, Wen Y, Soni PN, Gabrielli NM, Marcus EA, Ridge KM, Sachs G, Vazquez-Levin M, Sznajder JI, Vagin O, Dada LA. The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell-cell trans-dimerization of Na,K-ATPase beta1 subunits. J Cell Sci 129: 2394–2406, 2016. doi:10.1242/jcs.186148.Tokhtaeva E, Sun H, Deiss-Yehiely N, Wen Y, Soni PN, Gabrielli NM, Marcus EA, Ridge KM, Sachs G, Vazquez-Levin M, Sznajder JI, Vagin O, Dada LA. The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell-cell trans-dimerization of Na,K-ATPase beta1 subunits. J Cell Sci 129: 2394–2406, 2016. doi:10.1242/jcs.186148.Vadasz I, Sznajder JI. Gas exchange disturbances regulate alveolar fluid clearance during acute lung injury. Front Immunol 8: 757, 2017. doi:10.3389/fimmu.2017.00757.Vadasz I, Sznajder JI. Gas exchange disturbances regulate alveolar fluid clearance during acute lung injury. Front Immunol 8: 757, 2017. doi:10.3389/fimmu.2017.00757.Vagin O, Dada LA, Tokhtaeva E, Sachs G. The Na,K-ATPase alpha1beta1 heterodimer as a cell adhesion molecule in epithelia. Am J Physiol Cell Physiol 302: C1271–C1281, 2012. doi:10.1152/ajpcell.00456.2011.Vagin O, Dada LA, Tokhtaeva E, Sachs G. The Na,K-ATPase alpha1beta1 heterodimer as a cell adhesion molecule in epithelia. Am J Physiol Cell Physiol 302: C1271–C1281, 2012. doi:10.1152/ajpcell.00456.2011.Watanabe Y, Allen JD, Wrapp D, McLellan JS, Crispin M. Site-specific glycan analysis of the SARS-CoV-2 spike. Science 369: 330–333, 2020. doi:10.1126/science.abb9983.Watanabe Y, Allen JD, Wrapp D, McLellan JS, Crispin M. Site-specific glycan analysis of the SARS-CoV-2 spike. Science 369: 330–333, 2020. doi:10.1126/science.abb9983.Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 8: 475–481, 2020. [Erratum in Lancet Respir Med 8: e26, 2020]. doi:10.1016/S2213-2600(20)30079-5.Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 8: 475–481, 2020. [Erratum in Lancet Respir Med 8: e26, 2020]. doi:10.1016/S2213-2600(20)30079-5.Yin J, Michalick L, Tang C, Tabuchi A, Goldenberg N, Dan Q, Awwad K, Wang L, Erfinanda L, Nouailles G, Witzenrath M, Vogelzang A, Lv L, Lee WL, Zhang H, Rotstein O, Kapus A, Szaszi K, Fleming I, Liedtke WB, Kuppe H, Kuebler WM. Role of transient receptor potential vanilloid 4 in neutrophil activation and acute lung injury. Am J Respir Cell Mol Biol 54: 370–383, 2016. doi:10.1165/rcmb.2014-0225OCYin J, Michalick L, Tang C, Tabuchi A, Goldenberg N, Dan Q, Awwad K, Wang L, Erfinanda L, Nouailles G, Witzenrath M, Vogelzang A, Lv L, Lee WL, Zhang H, Rotstein O, Kapus A, Szaszi K, Fleming I, Liedtke WB, Kuppe H, Kuebler WM. Role of transient receptor potential vanilloid 4 in neutrophil activation and acute lung injury. Am J Respir Cell Mol Biol 54: 370–383, 2016. doi:10.1165/rcmb.2014-0225OC

The authors declare that there are no conflicts of interest present.