Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury with a high mortality rate. The renin-angiotensin system plays a crucial role in maintaining blood pressure and fluid balance, and angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) are key components of this system. ACE converts angiotensin I to angiotensin II, while ACE2 inactivates angiotensin II and acts as a negative regulator. ACE2 has also been identified as a potential receptor for the severe acute respiratory syndrome (SARS) coronavirus. This study investigates the role of ACE2 in ARDS. It was found that ACE2 and the angiotensin II type 2 receptor (AT2) protect mice from severe acute lung injury induced by acid aspiration or sepsis, while other components of the renin-angiotensin system, including ACE, angiotensin II, and the angiotensin II type 1a receptor (AT1a), promote disease progression, induce lung edema, and impair lung function. Key findings include: - Ace2-deficient mice showed significantly worse lung function, increased lung elastance, and more severe lung edema compared to wild-type mice. - Recombinant human ACE2 (rhUAACE2) treatment in Ace2-deficient mice improved lung function and reduced lung edema. - Genetic inactivation of Ace, but not Ace2, also reduced lung injury and improved outcomes. - Angiotensin II levels increased in the lungs and plasma of Ace2-deficient mice, suggesting that ACE2 deficiency leads to increased AngII production. - Pharmacological inhibition of the AT1 receptor attenuated lung injury in Ace2-deficient mice, indicating that AT1 receptor signaling is involved in the pathogenesis of acute lung injury. These results highlight the critical role of ACE2 in protecting against acute lung injury and suggest that targeting ACE2 could be a potential therapeutic strategy for ARDS.Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury with a high mortality rate. The renin-angiotensin system plays a crucial role in maintaining blood pressure and fluid balance, and angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) are key components of this system. ACE converts angiotensin I to angiotensin II, while ACE2 inactivates angiotensin II and acts as a negative regulator. ACE2 has also been identified as a potential receptor for the severe acute respiratory syndrome (SARS) coronavirus. This study investigates the role of ACE2 in ARDS. It was found that ACE2 and the angiotensin II type 2 receptor (AT2) protect mice from severe acute lung injury induced by acid aspiration or sepsis, while other components of the renin-angiotensin system, including ACE, angiotensin II, and the angiotensin II type 1a receptor (AT1a), promote disease progression, induce lung edema, and impair lung function. Key findings include: - Ace2-deficient mice showed significantly worse lung function, increased lung elastance, and more severe lung edema compared to wild-type mice. - Recombinant human ACE2 (rhUAACE2) treatment in Ace2-deficient mice improved lung function and reduced lung edema. - Genetic inactivation of Ace, but not Ace2, also reduced lung injury and improved outcomes. - Angiotensin II levels increased in the lungs and plasma of Ace2-deficient mice, suggesting that ACE2 deficiency leads to increased AngII production. - Pharmacological inhibition of the AT1 receptor attenuated lung injury in Ace2-deficient mice, indicating that AT1 receptor signaling is involved in the pathogenesis of acute lung injury. These results highlight the critical role of ACE2 in protecting against acute lung injury and suggest that targeting ACE2 could be a potential therapeutic strategy for ARDS.