Aquaporin-1 inhibition exacerbates ischemia-reperfusion-induced lung injury in mouse

Background: Ischemia-reperfusion injury (IRI), which involves severe inflammation and edema, is an inevitable feature of the lung transplantation process and leads to primary graft dysfunction (PGD). The activation of aquaporin 1 (AQP1) modulates fluid transport in the alveolar space. The current study investigated the role of AQP1 in ischemia-reperfusion (IR)-induced lung injury.Methods: A mouse model of lung IR was established by clamping the left lung hilar for 1 h and released for reperfusion for 24 h. The AQP1 inhibitor acetazolamide (AZA) was administered 3 days before lung ischemia with a dose of 100 mg/kg per day via gavage. Lung injury was evaluated using the ratio of wet-to-dry weight, peripheral bronchial epithelial thickness, degree of angioedema, acute lung injury score, neutrophil infiltration, and cytokine concentrations in bronchoalveolar lavage fluid.Results: Compared with sham treatment, ischemia with no reperfusion (IR 0h) and ischemia with reperfusion for 24 h (IR 24 h) significantly upregulated AQP1 expression, increased the wet/dry weight ratio, angioedema, neutrophil infiltration and cytokine production (interleukin-6 and tumor necrosis factor -a) and thickened the peripheral bronchial epithelium. AZA exacerbated inflammation and pulmonary edema. Conclusion: AQP1 may exert a protective effect against IR-induced lung injury, which could be attributed to alleviating pulmonary edema and inflammation. AQP1 upregulation might be a potential application to alleviate lung IRI and decrease the incidence of PGD.