(371) - Protective Effect of Imatinib on Ischemia-Reperfusion Injury in Rat Lung

Abstract

Ischemia-reperfusion injury (IRI) remains a significant complication after lung transplantation. Endothelial damage contributes to its development. Imatinib has recently been reported to regulate vascular permeability by protecting endothelium via inhibition of Abl and Abl-related gene (Arg) kinases under various permeability-inducing conditions. We hypothesized that imatinib could have a protective effect against IRI. Heparinized rat underwent left thoracotomy, and the left hilum was clamped for 90 minutes, followed by reperfusion for 120 minutes (rat hilar clamp model). Imatinib mesylate (50 mg/kg) and the solvent were intraperitoneally administered 20 min before ischemia in the Imatinib group and the Vehicle group, respectively (n=7, each). After reperfusion, lung mechanics, lung wet-to-dry weight ratio (W/D), and histological findings were obtained. The expression of vascular-endothelial cadherin (VEC) and the phosphorylation of CrkL, an exclusive target of Abl/Arg, were evaluated by Western blot analysis using lung tissue lysates. The cytokine levels in lung tissue were measured by ELISA. In the Imatinib group, lung mechanics were significantly improved (P<0.05). W/D was lower (P=0.01) and perivascular edema was ameliorated on histology. The number of neutrophils infiltrated into the lung was significantly decreased (P=0.02). The expression of VEC was maintained and pCrkL was inhibited by imatinib. The IL-10 level was significantly higher in the Imatinib group (P=0.008). In a rat IRI model, imatinib inhibited Abl/Arg in lung tissue, maintained endothelial junction with attenuated lung edema, increased anti-inflammatory cytokine, and showed less neutrophil infiltration. Imatinib demonstrated anti-permeability and anti-inflammatory effects in IRI; thus, it can be a novel treatment strategy.