title: Ischemic postconditioning during reperfusion attenuates intestinal injury and mucosal cell apoptosis by inhibiting JAK/STAT signaling activation.
abstract: The present study attempts to evaluate the role of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling in intestinal ischemia/reperfusion (I/R)-induced intestinal injury and whether immediate ischemic postconditioning ameliorates intestinal injury via attenuation of intestinal mucosal apoptosis subsequent to inhibiting JAK/STAT signaling activation. Anesthetized adult male Sprague-Dawley rats were subjected to superior mesenteric artery occlusion consisting of 60 min of ischemia and 2 h of reperfusion; sham laparotomy served as controls. Animals received either subcutaneous administration of JAK2 inhibitor (AG490, 8 mg/kg) or STAT inhibitor (rapamycin, 0.4 mg/kg) 30 min before ischemia. Ischemic postconditioning was performed by three cycles of 30-s reperfusion and 30-s ischemia initiated immediately upon reperfusion. It was found that intestinal I/R resulted in conspicuous intestinal injury evidenced by significant increases in Chiu's score, lactic acid, and diamine oxidase activity, accompanied with increases in plasma levels of 15-F2t-isoprostane, endothelin 1, and thromboxane B2, as well as increase in the intestinal tissue myeloperoxidase activity. Meanwhile, the apoptotic index and cleaved caspase 3, phosphorylated JAK2, phosphorylated STAT1, and phosphorylated STAT3 expression were significantly enhanced versus sham control. Both ischemic postconditioning and pretreatment with AG490 or rapamycin significantly attenuated all the above changes. These results indicate that JAK/STAT pathway activation plays a critical role in I/R-induced intestinal injury, which is associated with increased oxidative stress, neutrophil accumulation, intestinal mucosal apoptosis, and microcirculation disturbance. Ischemic postconditioning mediates attenuation of intestinal I/R injury, and cell apoptosis may be attributable to the JAK/STAT signaling inhibition.
authors: Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China.
authors: Shi-Hong
authors: SH
authors: Wen
authors: Yi
authors: Y
authors: Li
authors: Cai
authors: C
authors: Li
authors: Zhi-Qiu
authors: ZQ
authors: Xia
authors: Wei-Feng
authors: WF
authors: Liu
authors: Xu-Yu
authors: XY
authors: Zhang
authors: Wan-Long
authors: WL
authors: Lei
authors: Wen-Qi
authors: WQ
authors: Huang
authors: Ke-Xuan
authors: KX
authors: Liu
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D019332:Endothelin-1 / Q000097:blood; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019194:Ischemic Preconditioning; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019344:Lactic Acid / Q000097:blood; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C075750:8-epi-prostaglandin F2alpha; D019344:Lactic Acid; D013929:Thromboxane B2; D015237:Dinoprost; D006631:Amine Oxidase (Copper-Containing); C507927:Jak2 protein, rat; D053614:Janus Kinase 2; C505410:Casp3 protein, rat; D053148:Caspase 3; D020123:Sirolimus