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Systemic Bile Acids Affect the Severity of Acute Pancreatitis in Mice Depending on Their Hydrophobicity and the Disease Pathogenesis
Authors:Quang Trung Tran  Matthias Sendler  Mats L. Wiese  Julia Doller  Lukas Zierke  Marcel Gischke  Juliane Glaubitz  Van Huy Tran  Michael Lalk  Uwe T. Bornscheuer  Frank Ulrich Weiss  Markus M. Lerch  Ali A. Aghdassi
Affiliation:1.Department of Internal Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany;2.Department of Internal Medicine, University of Medicine and Pharmacy, Hue University, Hue City 530000, Vietnam;3.Institute of Biochemistry, University Greifswald, 17489 Greifswald, Germany;4.Ludwig Maximilian University Hospital, Ludwig Maximilian University of Munich, 81377 Munich, Germany
Abstract:Acute pancreatitis (AP) is a major, globally increasing gastrointestinal disease and a biliary origin is the most common cause. However, the effects of bile acids (BAs), given systemically, on the pancreas and on disease severity remains elusive. In this study, we have investigated the roles of different circulating BAs in animal models for AP to elucidate their impact on disease severity and the underlying pathomechanisms. BAs were incubated on isolated acini and AP was induced through repetitive injections of caerulein or L-arginine; pancreatic duct ligation (PDL); or combined biliopancreatic duct ligation (BPDL). Disease severity was assessed using biochemical and histological parameters. Serum cholecystokinin (CCK) concentrations were determined via enzyme immunoassay. The binding of the CCK1 receptor was measured using fluorescence-labeled CCK. In isolated acini, hydrophobic BAs mitigated the damaging effects of CCK. The same BAs further enhanced pancreatitis in L-arginine- and PDL-based pancreatitis, whereas they ameliorated pancreatic damage in the caerulein and BPDL models. Mechanistically, the binding affinity of the CCK1 receptor was significantly reduced by hydrophobic BAs. The hydrophobicity of BAs and the involvement of CCK seem to be relevant in the course of AP. Systemic BAs may affect the severity of AP by interfering with the CCK1 receptor.
Keywords:acute pancreatitis   bile acids   CCK1R binding   hydrophobicity
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