{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:35:26Z","timestamp":1789763726260,"version":"4.0.1"},"reference-count":87,"publisher":"American Physiological Society","issue":"3","funder":[{"name":"AlMahmeed Collaborative Research Award 2018","award":["ALM1801"],"award-info":[{"award-number":["ALM1801"]}]},{"DOI":"10.13039\/100012001","name":"Al Jalila Foundation Award","doi-asserted-by":"publisher","award":["AJF201763"],"award-info":[{"award-number":["AJF201763"]}],"id":[{"id":"10.13039\/100012001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Mohammed Bin Rashid University of Medicine and Health Sciences","award":["MBRU-CM-RG2018-05"],"award-info":[{"award-number":["MBRU-CM-RG2018-05"]}]},{"name":"Mohammed Bin Rashid University of Medicine and Health Sciences","award":["MBRU-CM-RG2018-04"],"award-info":[{"award-number":["MBRU-CM-RG2018-04"]}]},{"name":"Sandoq Al Watan Research & Development Grant","award":["SWARD-F2018-002"],"award-info":[{"award-number":["SWARD-F2018-002"]}]}],"content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2021,3,1]]},"abstract":"<jats:p>\n                    The tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, toward the host cells is determined, at least in part, by the expression and distribution of its cell surface receptor, angiotensin-converting enzyme 2 (ACE2). The virus further exploits the host cellular machinery to gain access into the cells; its spike protein is cleaved by a host cell surface transmembrane serine protease 2 (TMPRSS2) shortly after binding ACE2, followed by its proteolytic activation at a furin cleavage site. The virus primarily targets the epithelium of the respiratory tract, which is covered by a tightly regulated airway surface liquid (ASL) layer that serves as a primary defense mechanism against respiratory pathogens. The volume and viscosity of this fluid layer is regulated and maintained by a coordinated function of different transport pathways in the respiratory epithelium. We argue that SARS-CoV-2 may potentially alter evolutionary conserved second-messenger signaling cascades via activation of G protein-coupled receptors (GPCRs) or by directly modulating G protein signaling. Such signaling may in turn adversely modulate transepithelial transport processes, especially those involving cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial Na\n                    <jats:sup>+<\/jats:sup>\n                    channel (ENaC), thereby shifting the delicate balance between anion secretion and sodium absorption, which controls homeostasis of this fluid layer. As a result, activation of the secretory pathways including CFTR-mediated Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    transport may overwhelm the absorptive pathways, such as ENaC-dependent Na\n                    <jats:sup>+<\/jats:sup>\n                    uptake, and initiate a pathophysiological cascade leading to lung edema, one of the most serious and potentially deadly clinical manifestations of COVID-19.\n                  <\/jats:p>","DOI":"10.1152\/ajplung.00499.2020","type":"journal-article","created":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T15:08:17Z","timestamp":1610464097000},"page":"L430-L435","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":53,"title":["SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport"],"prefix":"10.1152","volume":"320","author":[{"given":"Reem","family":"Abdel 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