Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19

Abstract

A significant number of patients with coronavirus disease 2019 (COVID-19) develop acute respiratory distress syndrome (ARDS) that is associated with a poor outcome. The molecular mechanisms driving failure of the alveolar barrier upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain incompletely understood. The Na,K-ATPase is an adhesion molecule and a plasma membrane transporter that is critically required for proper alveolar epithelial function by both promoting barrier integrity and resolution of excess alveolar fluid, thus enabling appropriate gas exchange. However, numerous SARS-CoV-2-mediated and COVID-19-related signals directly or indirectly impair the function of the Na,K-ATPase, thereby potentially contributing to disease progression. In this Perspective, we highlight some of the putative mechanisms of SARS-CoV-2-driven dysfunction of the Na,K-ATPase, focusing on expression, maturation, and trafficking of the transporter. A therapeutic mean to selectively inhibit the maladaptive signals that impair the Na,K-ATPase upon SARS-CoV-2 infection might be effective in reestablishing the alveolar epithelial barrier and promoting alveolar fluid clearance and thus advantageous in patients with COVID-19-associated ARDS.

Keywords: COVID-19; Na,K-ATPase; SARS-CoV-2; alveolar epithelium; alveolar fluid clearance; lung edema.

Figure 1.

Schematic representation of mechanisms that may impair Na,K-ATPase function in COVID-19. SARS-CoV-2 may directly inhibit transcription, translation, maturation, and trafficking of the Na,K-ATPase, thus reducing the abundance and activity of the transporter at the plasma membrane. Sequels of COVID-19, such as gas exchange disturbances, uncontrolled inflammation, and activation of coagulation may additionally inhibit function of the Na,K-ATPase and lead to impaired alveolar epithelial barrier function and thus progressive respiratory failure. ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; PKC, protein kinase C; IL-6, interleukin-6; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α.