Abstract
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.
Highlights
Acute pancreatitis is an inflammatory disorder of the exocrine pancreas, which has a range of severity and causes considerable morbidity and mortality.[1]
Our findings demonstrate that lack of X-linked inhibitor of apoptosis protein (XIAP) promotes apoptosis and inhibits necrosis in acinar cells, decreases the pancreatic inflammatory response and ameliorates acute pancreatitis in mice through regulation of caspases, receptor-interacting protein kinase1 (RIP1) and Nuclear factor κB (NF-κB) activation
Morphological changes seen in pancreatitis including acinar cell vacuolization, inflammation, edema and acinar cell necrosis were significantly less severe in XIAP − / − mice as compared with wildtype mice (Figure 1)
Summary
Acute pancreatitis is an inflammatory disorder of the exocrine pancreas, which has a range of severity and causes considerable morbidity and mortality.[1]. Revealing the key signaling molecules that determine the pattern of pancreatic acinar cell death (apoptosis versus necrosis) in pancreatitis will provide potential molecular targets for effective therapy in this disease. The family of caspases is a major mediator of apoptosis in pancreatic acinar cells.[2] There are two main apoptotic pathways. Received 23.4.16; revised 10.1.17; accepted 24.1.17; Edited by M Agostini inhibitory mechanism is best characterized for the XIAP. It contains three BIR domains and a RING domain.[14,15]
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