Role of PI3K/Akt signaling pathway in dexmedetomidine-induced reduction of lung ischemia-reperfusion injury in rats undergoing cardiopulmonary bypass

Abstract

Objective To evaluate the role of PI3K/Akt signaling pathway in dexmedetomidine-induced reduction of lung ischemia-reperfusion (I/R) injury in rats undergoing cardiopulmonary bypass (CPB). Methods Twenty-four healthy adult male Sprague-Dawley rats, weighing 350-450 g, were divided into 3 groups (n=8 each) using a random number table method: group I/R, dexmedetomidine group (group D) and dexmedetomidine plus wortmannin group (group D+ W). Rats were anesthetized with pentobarbital sodium.Lung I/R was induced by clamping the left hilum of lung for 60 min starting from 10 min of CPB, followed by 120-min reperfusion.Dexmedetomidine was injected via the tail vein in a dose of 3 μg/kg at 10 min before clamping the left hilum of lung, followed by a continuous infusion of 1.5 μg·kg-1·h-1 until the end of CPB in group D. Dexmedetomidine was injected via the tail vein in a dose of 3 μg/kg at 10 min before clamping the left hilum of lung, followed by a continuous infusion of 1.5 μg·kg-1·h-1 until the end of CPB, and wortmannin was simultaneously injected via the tail vein in a dose of 15 μg/kg, followed by a continuous infusion of 2.0 μg·kg-1·min-1 until the end of CPB in group D+ W.Arterial blood samples were collected immediately before CPB (T1), immediately after opening the left hilum of lung (T2) and at 1.5 h after the end of CPB (T3), and oxygenation index (OI) and respiratory index (RI) were calculated.The rats were sacrificed at T3, and the left lung was removed for examination of the pathological changes which were scored and for determination of apoptosis rate (by flow cytometry) and Akt, Bad, activated caspase-3, phosphorylated Akt (p-Akt) and phosphorylated Bad (p-Bad) in lung tissues (by Western blot). Results Compared with the baseline at T1, OI was significantly decreased and RI was increased at T2 and T3 in the three groups (P<0.05). OI was significantly decreased and RI was increased at T3 than at T2 in the three groups (P<0.05). Compared with group I/R, OI was significantly increased and RI was decreased at T3, the pathological damage score and apoptosis rate were decreased, ratios of p-Akt/Akt and p-Bad/Bad were increased, and the expression of activated caspase-3 was down-regulated in group D, and OI was significantly decreased and RI was increased at T2 in group D+ W (P<0.05). Compared with group D, OI was significantly decreased and RI was increased at T3, the pathological damage score and apoptosis rate were increased, ratios of p-Akt/Akt and p-Bad/Bad were decreased, and the expression of activated caspase-3 was up-regulated in group D+ W (P<0.05). Conclusion Dexmedetomidine can reduce dexmedetomidine-induced reduction of lung I/R injury through activating PI3K/Akt signaling pathway and inhibiting cell apoptosis in rats undergoing CPB. Key words: Dexmedetomidine; 1-phosphatidylinositol 3-kinase; Protein-serine-threonine kinases; Cardiopulmonary bypass; Reperfusion injury; Lung