Abstract
Endoplasmic reticulum (ER) stress is a particular process with an imbalance of homeostasis, which plays an important role in pancreatitis, but little is known about how ER stress is implicated in severe acute pancreatitis (SAP) induced pancreatic beta-cell injury. To investigate the effect of 4-phenylbutyric acid (4-PBA) on the beta-cell injury following SAP and the underlying mechanism, twenty-four Sprague-Dawley rats were randomly divided into sham-operation (SO) group, SAP model group, and 4-PBA treatment group. SAP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. 4-PBA or normal saline was injected intraperitoneally for 3 days in respective group before successful modeling. Results showed that 4-PBA attenuated the following: (1) pancreas and islet pathological injuries, (2) serum TNF-α and IL-1β, (3) serum insulin and glucose, (4) beta-cell ultrastructural changes, (5) ER stress markers (BiP, ORP150, and CHOP), Caspase-3, and insulin expression in islet. These results suggested that 4-PBA mitigates pancreatic beta-cell injury and endocrine disorder in SAP, presumably because of its role in inhibiting excessive endoplasmic reticulum stress. This may serve as a new therapeutic target for reducing pancreatic beta-cell injury and endocrine disorder in SAP upon 4-PBA treatment.
Highlights
Severe acute pancreatitis (SAP) is an inflammatory disorder characterized by an intricate cascade of events originating from digestive enzyme activation in pancreas acinar cells [1–3]
Condensed chromatin concomitant with markedly dilated endoplasmic reticulum (ER) cisternae and increase of mitochondria damage in pancreatic beta cells were observed using Transmission Electron Microscopy (TEM) in SAP rats, and 4-phenylbutyric acid (4-PBA) eased the ultrastructural injury induced by SAP. These results suggested that ER stress responses, indicated by glucose regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) expression, in the pancreatic beta cells were greatly increased after SAP was induced. 4PBA could inhibit ER stress by suppressing expression of binding protein (BiP), ORP150, and CHOP, and Caspase-3, which is a key enzyme in the apoptosis process
The present study demonstrates that ER stress is involved in pancreatic beta-cell injury and pancreatic endocrine dysfunction after attack of severe acute pancreatitis
Summary
Severe acute pancreatitis (SAP) is an inflammatory disorder characterized by an intricate cascade of events originating from digestive enzyme activation in pancreas acinar cells [1–3]. Severe acute pancreatitis (SAP) is an inflammatory disorder characterized by an intricate cascade of events originating from digestive enzyme activation in pancreas acinar cells [1–. Pancreatic islets scatter among the acinar cells and consist mainly of beta cells which secrete insulin, the unique hormone lowering blood glucose level. ER stress is provoked by the accumulation of partially folded or misfolded proteins in the ER lumen [6] and activates unfolded protein response (UPR). Increasing evidence has demonstrated that ER stress and UPR are relevant in numerous pathophysiological disorders including sepsis [7], ulcerative colitis [8], rheumatoid arthritis [9], systemic lupus erythematosus [10], neurodegenerative diseases [11], diabetes mellitus [12], and viral infection [13]. The ER chaperone heavy chain binding protein (BiP), known as glucose regulated protein 78
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