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Infrarenal aortic cross-clamping (IAC) is a common procedure during infrarenal vascular operations. It often causes ischemia-reperfusion injury to lower limbs, resulting in systemic inflammation response and damage to remote organs (particularly lungs). Hydrogen sulfide (H2S) is a gaseous mediator that has been shown to have a protective effect against lung injury.Wistar rats underwent IAC for 2 hours, followed by 4 hours of reperfusion. GYY4137 (a slow-releasing H2S donor) and dl-propargylglycine (PAG, an inhibitor of cystathionine γ-lyase) were preadministered to rats 1 hour before IAC, and their effects on severity of lung injury and related mechanisms were investigated.IAC induced a significant increase in plasma levels of H2S, H2S-synthesizing activity, and cystathionine γ-lyase expression in lung tissues compared with sham operation. Administration of GYY4137 significantly increased the levels of H2S but had little effect on H2S-synthesizing activity, whereas PAG reduced H2S levels and H2S-synthesizing activity. Preadministration of GYY4137 significantly attenuated acute lung injury induced by IAC, evidenced by reduced histologic scores and wet lung contents; improved blood gas parameters; reduced cell counts and protein amounts in bronchoalveolar lavage fluids; and reduced myeloperoxidase activity in lung tissues and plasma levels of tumor necrosis factor α, interleukin 6, and interleukin 1β. However, PAG further aggravated the severity of lung injury and displayed opposite effects to GYY4137. In exploration of the mechanisms, we found that IAC increased the release of angiopoietin 2 (Ang2) and its expression in lung tissues. GYY4137 attenuated the increase of Ang2 release and expression and increased the phosphorylation of Akt and the activation of its downstream factors, glycogen synthase kinase 3β and ribosomal protein S6 kinase; PAG showed opposite effects.The study indicates that H2S may play a protective role in IAC-induced acute lung injury in rats by inhibiting inflammation and Ang2 release.The incidences of peripheral arterial diseases and aortic abdominal aneurysms are steadily increasing because of arteriosclerosis in the elderly. The postoperative morbidity of infrarenal vascular operations is closely linked to or accompanied by ischemia-reperfusion-induced injury and inflammation. This study provides a novel approach for alleviating acute lung injury induced by infrarenal aortic cross-clamping, which is a common procedure during infrarenal vascular operations. Given that hydrogen sulfide could protect multiple organs against several risk events, the results warrant further investigation by using GYY4137 in preventing acute lung injury during infrarenal vascular surgical interventions.