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

Abstract

IntroductionThe 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.MethodsSixty‐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‐aO2) were analyzed. The levels or activities of malondialdehyde, superoxidase dismutase, catalase, glutathione peroxidase, intracellular reactive oxygen species, tumor necrosis factor‐α, 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‐κB (NF‐κB) and their phosphorylated forms, and hypoxia‐inducible factor‐1α (HIF‐1α) were detected. Histological changes were observed using hematoxylin and eosin staining. Moreover, the survival rate following pulmonary I/R injury was recorded daily.ResultsPare significantly increased the OI, decreased the PA‐aO2, 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‐κB, further increased HIF‐1α expression, and significantly improved the rat survival rate.ConclusionsPare pretreatment attenuated lung I/R injury by inhibiting oxidative stress and the inflammatory response possibly via inhibiting the activation of the ERK/NF‐κB pathway and further activating the HIF‐1α pathway.