Acute pancreatitis in aging animals:Loss of pancreatitis-associated protein protection?

AIM:To investigate the effect of age on severity of acute pancreatitis(AP) using biochemical markers,histology and expression of the protective pancreatitisassociated proteins(PAPs).METHODS:AP was induced via intraductal injection of 4% sodium taurocholate in young and old rats.Sera and pancreata were assayed at 24 h for the parameters listed above;we also employed a novel molecular technique to assess bacterial infiltration using polymerase chain reaction to measure bacterial genomic ribosomal RNA.RESULTS:At 24 h after induction of AP,the pancreata of older animals had less edema(mean ± SE histologic score of young vs old:3.11 ± 0.16 vs 2.50 ±-0.11,P < 0.05),decreased local inflammatory response(histologic score of stromal infiltrate:3.11 ± 0.27 vs 2.00 ± 0.17,P < 0.05) and increased bacterial infiltration(174% ± 52% increase from sham vs 377% ± 4%,P < 0.05).A decreased expression of PAP1 and PAP2 was demonstrated by Western blotting analysis and immunohistochemical staining.There were no differences in serum amylase and lipase activity,or tissue myeloperoxidase or monocyte chemotactic protein-1 levels.However,in the most-aged group,serum C-reactive protein levels were higher(young vs old:0.249 ± 0.04 mg/dL vs 2.45 ± 0.68 mg/dL,P < 0.05).CONCLUSION:In older animals,there is depressed PAP expression related to a blunted inflammatory response in AP which is associated with worsened bacterial infiltration and higher C-reactive protein level;this may explain the more aggressive clinical course.

Acinar cell injury induced by inadequate unfolded protein response in acute pancreatitis

Acute pancreatitis (AP) is an inflammatory disorder of pancreatic tissue initiated in injured acinar cells. Severe AP remains a significant challenge due to the lack of effective treatment. The widely-accepted autodigestion theory of AP is now facing challenges, since inhibiting protease activation has negligible effectiveness for AP treatment despite numerous efforts. Furthermore, accumulating evidence supports a new concept that malfunction of a self-protective mechanism, the unfolded protein response(UPR), is the driving force behind the pathogenesis of AP. The UPR is induced by endoplasmic reticulum(ER) stress, a disturbance frequently found in acinar cells, to prevent the aggravation of ER stress that can otherwise lead to cell injury. In addition, the UPR's signaling pathways control NFκB activation and autophagy flux, and these dysregulations cause acinar cell inflammatory injury in AP, but with poorly understood mechanisms. We therefore summarize the protective role of the UPR in AP, propose mechanistic models of how inadequate UPR could promote NFκB's pro-inflammatory activity and impair autophagy's protective function in acinar cells, and discuss its relevance to current AP treatment. We hope that insight provided in this review will help facilitate the research and management of AP.

Mechanisms of interleukin-22's beneficial effects in acutepancreatitis

Acute pancreatitis(AP) is a disorder characterized by parenchymal injury of the pancreas controlled by immune cell-mediated inflammation. AP remains a significant challenge in the clinic due to a lack of specific and effective treatment. Knowledge of the complex mechanisms that regulate the inflammatory response in AP is needed for the development of new approaches to treatment, since immune cell-derived inflammatory cytokines have been recognized to play critical roles in the pathogenesis of the disease. Recent studies have shown that interleukin(IL)-22, a cytokine secreted by leukocytes, when applied in the severe animal models of AP, protects against the inflammation-mediated acinar injury. In contrast, in a mild AP model, endogenous IL-22 has been found to be a predominantly antiinflammatory mediator that inhibits inflammatory cell infiltration via the induction of Reg3 proteins in acinar cells, but does not protect against acinar injury in the early stage of AP. However, constitutively over-expressed IL-22 can prevent the initial acinar injury caused by excessive autophagy through the induction of the antiautophagic proteins Bcl-2 and Bcl-XL. Thus IL-22 plays different roles in AP depending on the severity of the AP model. This review focuses on these recently reported findings for the purpose of better understanding IL-22's regulatory roles in AP which could help to develop a novel therapeutic strategy.

Role of regenerating islet-derived proteins in inflammatory bowel disease

Inflammatory bowel disease(IBD)is an inflammatory disorder of the gastrointestinal tract that affects millions of patients worldwide.It has a complex and multifactorial etiology leading to excessive exposure of intestinal epithelium to microbial antigens,inappropriate activation of the immune system and ultimately to the damage of intestinal tissues.Although numerous efforts have been made to improve the disease management,IBD remains persistently recurring and beyond cure.This is due largely to the gaps in our understanding of the pathogenesis of IBD that hamper the development of timely diagnoses and effective treatment.However,some recent discoveries,including the beneficial effects of interleukin-22(IL-22)on the inflamed intestine,have shed light on a self-protective mechanism in IBD.Regenerating islet-derived(REG/Reg)proteins are small secretory proteins which function as IL-22’s downstream effectors.Mounting studies have demonstrated that IBD patients have significantly increased REG expressions in the injured intestine,but with undefined mechanisms and roles.The reported functions of REG/Reg proteins in intestinal homeostasis,such as those of antibacterial,anti-inflammatory and tissue repair,lead us to discuss their potential mechanisms and clinical relevance in IBD in order to advance IBD research and management.