15-Deoxy-△12,14-prostaglandin J2 alleviates hepatic ischemia-reperfusion injury in mice via inducing antioxidant response and inhibiting apoptosis and autophagy

摘要

Hepatic ischemia-reperfusion (I/R) injury is a common clinical impairment that occurs in many circumstances and leads to poor prognosis.Both apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury.15-Deoxy-△12,14-prostaglandin J2 (15d-PGJ2) is one of the best-studied anti-inflammatory prostaglandins,which has been verified to exert antiinflammatory and cell-protective functions in various types of cells and animal models.In this study we explored the effects of 15d-PGJ2 on both apoptosis and autophagy in mouse hepatic I/R injury and its possible mechanisms.A model of segmental (70％) hepatic warm ischemia was established in Balb/c mice,and the pathological changes in serum and liver tissues were detected at 6,12,and 24 h post-surgery,while 15d-PGJ2 (2.5,7.5,15 pg,iv) was administered 30 min prior the surgery.Pretreatment with 15d-PGJ2 (7.5,15 μg) significantly ameliorated VR-induced hepatic injury evidenced by dose-dependent reduction of serum ALT and AST levels as well as alleviated tissue damages.15d-PGJ2 pretreatment significantly decreased the serum TNF-α and IL-1β levels and the hepatic expression of F4/80,a major biomarker of macrophages.15d-PGJ2 pretreatment upregulated the Bcl-2/Bax ratio,thus reducing the number of apoptotic cells in the livers.15d-PGJ2 pretreatment considerably suppressed the expression of Beclin-1 and LC3,thus decreasing the number of autophagosomes in the livers.Furthermore,15d-PGJ2 pretreatment activated Nrf2 and inhibited a ROS/HIF1α/BNIP3 pathway in the livers.Pretreatment with the PPARy receptor blocker GW9662 (2 μg,ip) partly reversed the protective effects of 15d-PGJ2 on hepatic I/R injury.In conclusion,our results confirm the protective effect of 15d-PGJ2 on hepatic I/R injury,an effect that may rely on a reduction in the activation of Kupffer cells and on activation of the Nrf2 pathway,which lead to inhibition of ROS generation,apoptosis,and autophagy.