Parecoxib sodium alleviates ischemia reperfusion-induced pulmonary injury via inhibiting ERK/NF-κB and further activating the HIF-1α pathway

Introduction: The lungs are extremely vulnerable to ischemia/reperfusion (I/R), which is characterized by intense inflammation, oxidative stress, alveolar damage, and vascular permeability. Parecoxib sodium (Pare) has been shown to exert protective effects against multiple I/R-induced tissue injuries. However, its role in I/R-induced lung injury remains unknown. This study aimed to reveal the roles and mechanisms of Pare in pulmonary I/R injury. Methods: Sixty-six rats were randomly divided into three groups: The sham-operated group, the pulmonary I/R group, and the Pare-pretreated I/R group. Pare at 10 mg/kg or saline (vehicle control) were intraperitoneally administered to rats once per day for 5 consecutive days before ischemia. Serum and tissue samples were harvested following 2 h of reperfusion. The oxygenation index (OI) and alveolar-arterial oxygen partial pressure difference (PA-aO(2)) were analyzed. The levels or activities of malondialdehyde, superoxidase dismutase, catalase, glutathione peroxidase, intracellular reactive oxygen species, tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8 were examined. The mitochondrial membrane potential was measured. The protein expression levels of the extracellular signal-regulated kinase (ERK), nuclear factor-kappa B (NF-kappa B) and their phosphorylated forms, and hypoxia-inducible factor-1 alpha (HIF-1 alpha) were detected. Histological changes were observed using hematoxylin and eosin staining. Moreover, the survival rate following pulmonary I/R injury was recorded daily. Results: Pare significantly increased the OI, decreased the PA-aO(2), increased the levels of antioxidants, while decreasing the levels of oxidants, and alleviated mitochondrial dysfunction and the histopathological damage induced by I/R. Furthermore, Pare inhibited the expression of proinflammatory cytokines, suppressed the activation of ERK and NF-kappa B, further increased HIF-1 alpha expression, and significantly improved the rat survival rate. Conclusions: Pare pretreatment attenuated lung I/R injury by inhibiting oxidative stress and the inflammatory response possibly via inhibiting the activation of the ERK/NF-kappa B pathway and further activating the HIF-1 alpha pathway.