Hydrogen sulfide ameliorates acute lung injury induced by infrarenal aortic cross-clamping by inhibiting inflammation and angiopoietin 2 release.

Abstract

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.