Liu Yong, Chen Xiao-Dong, Yu Jiang, Chi Jun-Lin, Long Fei-Wu, Yang Hong-Wei, Chen Ke-Ling, Lv Zhao-Ying, Zhou Bin, Peng Zhi-Hai, Sun Xiao-Feng, Li Yuan, Zhou Zong-Guang
Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China.
Cell Death Dis. 2017 Mar 16;8(3):e2685. doi: 10.1038/cddis.2017.70.
Severe acute pancreatitis (SAP) still remains a clinical challenge, not only for its high mortality but the uncontrolled inflammatory progression from acute pancreatitis (AP) to SAP. Cell death, including apoptosis and necrosis are critical pathology of AP, since the severity of pancreatitis correlates directly with necrosis and inversely with apoptosis Therefore, regulation of cell death from necrosis to apoptosis may have practicably therapeutic value. X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the inhibitor of apoptosis proteins (IAP) family, but its function in AP remains unclear. In the present study, we investigated the potential role of XIAP in regulation of cell death and inflammation during acute pancreatitis. The in vivo pancreatitis model was induced by the administration of cerulein with or without lipopolysaccharide (LPS) or by the administration of l-arginine in wild-type or XIAP-deficient mice, and ex vivo model was induced by the administration of cerulein+LPS in AR42J cell line following XIAP inhibition. The severity of acute pancreatitis was determined by serum amylase activity and histological grading. XIAP deletion on cell apoptosis, necrosis and inflammatory response were examined. Caspases activities, nuclear factor-κB (NF-κB) activation and receptor-interacting protein kinase1 (RIP1) degradation were assessed by western blot. Deletion of XIAP resulted in the reduction of amylase activity, decrease of NF-κB activation and less release of TNF-α and IL-6, together with increased caspases activities and RIP1 degradation, leading to enhanced apoptosis and reduced necrosis in pancreatic acinar cells and ameliorated the severity of acute pancreatitis. Our results indicate that deletion of XIAP switches cell death away from necrosis to apoptosis and decreases the inflammatory response, effectively attenuating the severity of AP/SAP. The critical role of XIAP in cell death and inflammation suggests that inhibition of XIAP represents a potential therapeutic strategy for the treatment of acute pancreatitis.
重症急性胰腺炎（SAP）仍然是一项临床挑战，这不仅是因为其高死亡率，还在于从急性胰腺炎（AP）到SAP的炎症进展难以控制。细胞死亡，包括凋亡和坏死，是AP的关键病理过程，因为胰腺炎的严重程度与坏死直接相关，与凋亡呈负相关。因此，将细胞死亡从坏死调节为凋亡可能具有实际的治疗价值。X连锁凋亡抑制蛋白（XIAP）是凋亡抑制蛋白（IAP）家族中特征最明确的成员，但其在AP中的功能仍不清楚。在本研究中，我们调查了XIAP在急性胰腺炎期间调节细胞死亡和炎症中的潜在作用。通过在野生型或XIAP缺陷小鼠中给予雨蛙肽（有或无脂多糖（LPS））或给予L-精氨酸来诱导体内胰腺炎模型，通过在XIAP抑制后在AR42J细胞系中给予雨蛙肽+LPS来诱导体外模型。通过血清淀粉酶活性和组织学分级来确定急性胰腺炎的严重程度。检测XIAP缺失对细胞凋亡、坏死和炎症反应的影响。通过蛋白质印迹法评估半胱天冬酶活性、核因子-κB（NF-κB）激活和受体相互作用蛋白激酶1（RIP1）降解。XIAP缺失导致淀粉酶活性降低、NF-κB激活减少以及TNF-α和IL-6释放减少，同时半胱天冬酶活性增加和RIP1降解，导致胰腺腺泡细胞凋亡增加、坏死减少，并改善了急性胰腺炎的严重程度。我们的结果表明，XIAP缺失使细胞死亡从坏死转变为凋亡，并减少炎症反应，有效减轻AP/SAP的严重程度。XIAP在细胞死亡和炎症中的关键作用表明，抑制XIAP代表了一种治疗急性胰腺炎的潜在策略。
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