Abstract SARS‐CoV‐2 uptake by lung epithelial cells is a critical step in the pathogenesis of COVID‐19. Viral entry is dependent on the binding of the viral spike protein to the angiotensin converting enzyme II protein (ACE2) on the host cell surface, followed by proteolytic cleavage by a host serine protease such as TMPRSS2. Infection of alveolar epithelial cells (AEC) in the distal lung is a key feature in progression to the acute respiratory distress syndrome (ARDS). We hypothesized that AEC expression of ACE2 is induced by hypoxia. In a murine model of hypoxic stress (12% FiO2), the total lung Ace2 mRNA and protein expression was significantly increased after 24 hours in hypoxia compared to normoxia (21% FiO2). In experiments with primary murine type II AEC, we found that exposure to hypoxia either in vivo (prior to isolation) or in vitro resulted in greatly increased AEC expression of both Ace2 (mRNA and protein) and of Tmprss2. However, when isolated type II AEC were maintained in culture over 5 days, with loss of type II cell characteristics and induction of type I cell features, Ace2 expression was greatly reduced, suggesting that this expression was a feature of only this subset of AEC. Finally, in primary human small airway epithelial cells (SAEC), ACE2 mRNA and protein expression were also induced by hypoxia, as was binding to purified spike protein. Hypoxia‐induced increase in ACE2 expression in type II AEC may provide an explanation of the extended temporal course of human patients who develop ARDS in COVID‐19. This figure shows relative ACE2 mRNA expression in lung homogenate and isolated type II alveolar epithelial cells from mice exposed to a hypoxic environment compared to control mice in normoxia. Hypoxic exposure in vivo results in significant increased expression of type II cell ACE2 and TMPRSS2. These data suggest a mechanism by which hypoxia facilitates entry of SARS‐CoV‐2 into alveolar epithelial cells.
【저자키워드】 TMPRSS2, 【초록키워드】 ACE2, ARDS, Pathogenesis, Stress, hypoxia, lung, progression, in vitro, Spike protein, COVID‐19, SARS‐CoV‐2, Protein, Characteristics, Features, Culture, mice, mRNA, Patient, Isolation, murine model, experiment, in vivo, ACE2 expression, expression, Critical, mechanism, binding, acute respiratory distress, alveolar epithelial cells, viral spike protein, FiO2, increased expression, host serine protease, type I, ACE2 mRNA, syndrome, protein expression, proteolytic cleavage, normoxia, murine, Cell, hypoxic, host cell surface, significantly increased, Course, develop, reduced, facilitate, dependent on, increase in, subset, purified, lung epithelial cell, alveolar epithelial cell, 24 hour, AEC, airway epithelial cell, distal, enzyme II, hypoxic environment, 【제목키워드】 Pathogenesis, acute lung injury, COVID‐19, expression, epithelial, alveolar, induce, enzyme II,