Abstract: Objective To explore the protective potential and mechanism of angiotensin-converting enzyme II (ACE2) in acute lung injury (ALI) induced by limb ischemia reperfusion in mice. Methods Male wild-type and ACE2 transgenic mice (overexpression of ACE2) Institute of Cancer Research mice were randomly divided into six groups (n =18): wild control group (Control), wild model group (Model), ACE2 control group (ACE2 + Control), ACE2 model group (ACE2 + Model), ACE2 model + A779 group (ACE2 + Model + A779), and ACE2 model + MLN-4760 group (ACE2 + Model + MLN-4760). ALI models were established using rubber band ligation of the bilateral hind limb roots (ischemia for 2 h and reperfusion for 4 h). Lung histological changes were observed using hematoxylin and eosin (HE) staining. Lung water content and pulmonary permeability were indicated by the organ coefficient, wet-to-dry weight ratio, cell numbers, and protein concentration in the bronchoalveolar lavage fluid (BALF). Enzyme-linked immunosorbent assay was used to determine the concentrations of BALF interleukin ( IL) - 6, tumor necrosis factor ( TNF) - α, and lung angiotensin II (Ang II) / angiotensin-(1-7) [Ang-(1-7)]. Quantitative real-time polymerase chain reaction was used to analyze mRNA expression of ACE/ ACE2, and western blot used to quantify the protein expression of ACE/ ACE2 and AT1 / Mas receptors. Results Compared with the wild model group, overexpression of ACE2 attenuated lung lesions ( HE staining and lung injury score), reduced alveolar capillary permeability (organ coefficient, wet-to-dry weight ratio, BALF cell numbers, protein concentration), improved the expression profiles of inflammatory cytokines (IL-6 and TNF-α) in the BALF, and (particularly) reversed pulmonary renin-angiotensin system imbalance. Moreover, these effects were abrogated by MLN-4760 (a specific ACE2 inhibitor) and A779 ( a specific Mas receptor antagonist). Conclusions The findings indicate that ACE2 can ameliorate the imbalance of the pulmonary renin-angiotensin system and the ALI via the ACE2-Ang- (1-7)-Mas axis.