title: Lipoxin A4 Preconditioning Attenuates Intestinal Ischemia Reperfusion Injury through Keap1/Nrf2 Pathway in a Lipoxin A4 Receptor Independent Manner.
abstract: Oxidative stress plays a critical role in the pathogenesis of intestinal ischemia reperfusion (IIR) injury. Enhancement in endogenous Lipoxin A4 (LXA4), a potent antioxidant and mediator, is associated with attenuation of IIR. However, the effects of LXA4 on IIR injury and the potential mechanisms are unknown. In a rat IIR (ischemia 45 minutes and subsequent reperfusion 6 hours) model, IIR caused intestinal injury, evidenced by increased serum diamine oxidase, D-lactic acid, intestinal-type fatty acid-binding protein, and the oxidative stress marker 15-F2t-Isoprostane. LXA4 treatment significantly attenuated IIR injury by reducing mucosal 15-F2t-Isoprostane and elevating endogenous antioxidant superoxide dismutase activity, accompanied with Keap1/Nrf2 pathway activation. Meanwhile, LXA4 receptor antagonist Boc-2 reversed the protective effects of LXA4 on intestinal injury but failed to affect the oxidative stress and the related Nrf2 pathway. Furthermore, Nrf2 antagonist brusatol reversed the antioxidant effects conferred by LXA4 and led to exacerbation of intestinal epithelium cells oxidative stress and apoptosis, finally resulting in a decrease of survival rate of rat. Meanwhile, LXA4 pretreatment upregulated nuclear Nrf2 level and reduced hypoxia/reoxygenation-induced IEC-6 cell damage and Nrf2 siRNA reversed this protective effect of LXA4 in vitro. In conclusion, these findings suggest that LXA4 ameliorates IIR injury by activating Keap1/Nrf2 pathway in a LXA4 receptor independent manner.
authors.affiliation: Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510000, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, Pokfulam 999077, Hong Kong.
authors.forename: Zipeng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, Pokfulam 999077, Hong Kong.
authors.forename: Haobo
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The Second Affiliated Hospital of Jinan University, Shenzhen 51000, China.
authors.forename: Zhong-Jun
authors.initials: ZJ
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China.
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Hei
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, Pokfulam 999077, Hong Kong; Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China.
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D015237:Dinoprost / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D050556:Fatty Acid-Binding Proteins / Q000097:blood; D007422:Intestines / Q000473:pathology; D028421:Isoprostanes / Q000032:analysis; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D019344:Lactic Acid / Q000097:blood; D044045:Lipoxins / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008856:Microscopy, Fluorescence; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044067:Receptors, Lipoxin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D013482:Superoxide Dismutase / Q000032:analysis
chemical_list: D000975:Antioxidants; D050556:Fatty Acid-Binding Proteins; D028421:Isoprostanes; D000072019:Kelch-Like ECH-Associated Protein 1; D044045:Lipoxins; D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering; D044067:Receptors, Lipoxin; C482540:lipoxin A(4) receptor, rat; C040527:lipoxin A4; C075750:8-epi-prostaglandin F2alpha; D019344:Lactic Acid; D015237:Dinoprost; D013482:Superoxide Dismutase