title: 15-Deoxy-Δ12,14-prostaglandin J2alleviates hepatic ischemia-reperfusion injury in mice via inducing antioxidant response and inhibiting apoptosis and autophagy.
abstract: 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-Δ12,14-prostaglandin J2(15d-PGJ2) is one of the best-studied anti-inflammatory prostaglandins, which has been verified to exert anti-inflammatory 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 μg, iv) was administered 30 min prior the surgery. Pretreatment with 15d-PGJ2 (7.5, 15 μg) significantly ameliorated I/R-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 PPARγ 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.
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Kan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Sai-Nan
authors.initials: SN
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Wei-Qi
authors.initials: WQ
authors.lastname: Dai
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Xia
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Ying-Qun
authors.initials: YQ
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Chuan-Yong
authors.initials: CY
authors.lastname: Guo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D007728:Kupffer Cells / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020011:Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000975:Antioxidants; D020011:Protective Agents; D017382:Reactive Oxygen Species; D015230:Prostaglandin D2