OBJECTIVE: This research aims to investigate the role and mechanism of PI3K/Akt pathway in the pathological process of lung ischemia-reperfusion injury in dexmedetomidine-treated rats. MATERIALS AND METHODS: Forty-five healthy male Sprague-Dawley rats were divided into three groups: sham operation group, lung ischemia-reperfusion group (IR group) and dexmedetomidine pretreatment group (Dex group). Rats in the sham operation group did not receive other procedures except for opening left chest. The left lung hilar of rats in the IR group was clamped with non-invasive vascular clamp after anesthesia to establish an ischemic model. After 1 hour, the vascular clamp was released and the rats were reperfused for 2 hours. As for rats in the Dex group, 3 mu g/kg of dexmedetomidine (pumping time of 10 min) was pumped through the tail vein before releasing the left hilar clamp. After the experiment, blood samples and lung tissues were collected. Serum levels of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha). IL-10, and IL-1 in rats were examined. Activities of malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT) in rat lung tissues were also detected. Besides, the expressions of hypoxia-inducible factor-la (HIF-la), p-Akt, Caspase-3, and Caspase-9 in lung tissues were detected by Western blot. The mRNA expression levels of HIF-1a, p-Akt. Caspase-3, and Caspase-9 in lung tissues were evaluated by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). RESULTS: Lung ischemia-reperfusion markedly increased the levels of IL-6, TNF-alpha, IL-10, and IL-1 in the IR group. In contrast, dexmedetomidine pretreatment decreased the expression levels of IL-6, TNF-alpha, IL-10, and IL-1in the Dex group. Also, the activities of MDA and MPO in lung tissues of rats in the IR group significantly increased after lung ischemia-reperfusion injury, whereas dexmedetomidine pretreatment reversed the elevated activities of MDA and MPO in the Dex group. Furthermore, dexmedetomidine pretreatment also improved the activities of SOD and CAT in rat lung tissues compared with rats with lung ischemia-reperfusion injury. In addition, dexmedetomidine pretreatment increased the expression levels of HIF-l alpha, p-Akt and HIF- in the Dex group when compared to those in the IR group. The mRNA expressions of HIF-1a, p-Akt, Caspase-3, and Caspase-9 in lung tissue of rats was significantly reduced after dexmedetomidine pretreatment. CONCLUSIONS: Rat lung ischemia-reperfusion can induce severe lung injury. Dexmedetomidine treatment can attenuate lung ischemia-reperfusion injury by activating the PI3K/Akt signaling pathway at the transcriptional level.