title: Inhibition of the nucleotide-binding domain, leucine-rich containing family, pyrin-domain containing 3 inflammasome reduces the severity of experimentally induced acute pancreatitis in obese mice.
abstract: 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.
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Ill. Electronic address: jmyork@uic.edu.
authors.forename: Jason M
authors.initials: JM
authors.lastname: York
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Ill.
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Castellanos
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Ill.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cabay
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Ill.
authors.forename: Giamila
authors.initials: G
authors.lastname: Fantuzzi
mesh_terms: D000681:Amylases / Q000097:blood / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008049:Lipase / Q000097:blood / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010195:Pancreatitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D008049:Lipase; D000681:Amylases; D005905:Glyburide