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Acute pancreatitis (AP), although most often a mild and self-limiting inflammatory disease, worsens to a characteristically necrotic severe acute pancreatitis (SAP) in about 20% of cases. Obesity, affecting more than one-third of American adults, is a risk factor for the development of SAP, but the exact mechanism of this association has not been identified. Coincidental with chronic low-grade inflammation, activation of the nucleotide-binding domain, leucine-rich containing family, pyrin-domain containing 3 (NLRP3) inflammasome increases with obesity. Lean mice genetically deficient in specific components of the NLRP3 inflammasome are protected from experimentally induced AP, indicating a direct involvement of this pathway in AP pathophysiology. We hypothesized that inhibition of the NLRP3 inflammasome with the sulfonylurea drug glyburide would reduce disease severity in obese mice with cerulein-induced SAP. Treatment with glyburide led to significantly reduced relative pancreatic mass and water content and less pancreatic damage and cell death in genetically obese ob/ob mice with SAP compared with vehicle-treated obese SAP mice. Glyburide administration in ob/ob mice with cerulein-induced SAP also resulted in significantly reduced serum levels of interleukin 6, lipase, and amylase and led to lower production of lipopolysaccharide-stimulated interleukin 1β release in cultured peritoneal cells, compared with vehicle-treated ob/ob mice with SAP. Together, these data indicate involvement of the NLRP3 inflammasome in obesity-associated SAP and expose the possible utility of its inhibition in prevention or treatment of SAP in obese individuals.

G A A b st ra ct s pancreatic stellate cells (PSCs), which plays a crucial role in the pathogenesis of CP. [Materials and Methods] In vivo, 3 weeks old Wistar rat and WBN/KOB (KOB) rats were fed control diet (CD) or high-fat diet (HFD). After 4 weeks treatment, blood samples and pancreatic tissues were extracted. In vitro, PSCs were isolated from the male Wistar rat, and incubated with palmitic acid (50 to 200μM) in the presence or absence of GSK2606414 which inhibits phosphorylation of PERK (PKR-like ER kinase) as a sensor of ER stress. Histological change was examined by microscopic finding. Both in vivo and in vitro, expressions of fibrosisrelated mRNA (type I collagen, fibronectin, TGF-beta) and ER stress-related mRNA [glucose related protein 78 (Grp78), Grp94, Activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP)] were evaluated by quantitative RT-PCR. Cell proliferation was evaluated by MTS assay. [Results] Fibrosis and ER stress-related mRNA expressions in CD-fed KOB rats were significantly higher than CD-fed Wistar rats. But in PSCs, there were no difference in ER-stress related mRNA expressions between 1st and 3rd passage, suggesting that PSCs activation itself do not induce ER stress. HFD treatment increased serum fatty acid levels and ER stress-related mRNA expressions in KOB rats, though fibrotic area, alphaSMA expression in the stromal area and fibrosis-related mRNA expressions were reduced. Palmitic acid stimulation increased ER stress-relatedmRNA expressions but reduced proliferation and fibrosis-related mRNA expressions in PSCs. All of these effects were inhibited in the presence of GSK2606414. [Conclusions] Our findings demonstrated that ER stress response induced by saturated fatty acid impairs proliferation and extracellular matrix synthesis in PSCs, resulting in the inhibition of fibrogenesis of CP. Moreover, fatty acid may not promote the pathogenesis of CP at least in the early stage.