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Complement Component 5 Mediates Development of Fibrosis, via Activation of Stellate Cells, in 2 Mouse Models of Chronic Pancreatitis.
Sendler, Matthias; Beyer, Georg; Mahajan, Ujjwal M; Kauschke, Vivien; Maertin, Sandrina; Schurmann, Claudia; Homuth, Georg; Völker, Uwe; Völzke, Henry; Halangk, Walter; Wartmann, Thomas; Weiss, Frank-Ulrich; Hegyi, Peter; Lerch, Markus M; Mayerle, Julia.
Afiliación
  • Sendler M; Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Beyer G; Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Mahajan UM; Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Kauschke V; Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Maertin S; Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Schurmann C; Interfaculty Institutes for Genetics and Functional Genomics, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Homuth G; Interfaculty Institutes for Genetics and Functional Genomics, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Völker U; Interfaculty Institutes for Genetics and Functional Genomics, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Völzke H; Institute for Community Medicine, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Halangk W; Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
  • Wartmann T; Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
  • Weiss FU; Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Hegyi P; First Department of Medicine, University of Szeged, Szeged, Hungary; MTA-SZTE Lendulet Translational Gastroenterology Research Group, Szeged, Hungary.
  • Lerch MM; Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
  • Mayerle J; Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany. Electronic address: mayerle@uni-greifswald.de.
Gastroenterology ; 149(3): 765-76.e10, 2015 Sep.
Article en En | MEDLINE | ID: mdl-26001927
BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of chronic pancreatitis. We investigated the roles of complement component 5 (C5) in pancreatic fibrogenesis in mice and patients. METHODS: Chronic pancreatitis was induced by ligation of the midpancreatic duct, followed by a single supramaximal intraperitoneal injection of cerulein, in C57Bl6 (control) and C5-deficient mice. Some mice were given injections of 2 different antagonists of the receptor for C5a over 21 days. In a separate model, mice were given injections of cerulein for 10 weeks to induce chronic pancreatitis. Direct effects of C5 were studied in cultured primary cells. We performed genotype analysis for the single-nucleotide polymorphisms rs 17611 and rs 2300929 in C5 in patients with pancreatitis and healthy individuals (controls). Blood cells from 976 subjects were analyzed by transcriptional profiling. RESULTS: During the initial phase of pancreatitis, levels of pancreatic damage were similar between C5-deficient and control mice. During later stages of pancreatitis, C5-deficient mice and mice given injections of C5a-receptor antagonists developed significantly less pancreatic fibrosis than control mice. Primary pancreatic stellate cells were activated in vitro by C5a. There were no differences in the rs 2300929 SNP between subjects with or without pancreatitis, but the minor allele rs17611 was associated with a significant increase in levels of C5 in whole blood. CONCLUSIONS: In mice, loss of C5 or injection of a C5a-receptor antagonist significantly reduced the level of fibrosis of chronic pancreatitis, but this was not a consequence of milder disease in early stages of pancreatitis. C5 might be a therapeutic target for chronic pancreatitis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complemento C5 / Pancreatitis Crónica / Células Estrelladas Pancreáticas Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Gastroenterology Año: 2015 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complemento C5 / Pancreatitis Crónica / Células Estrelladas Pancreáticas Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Gastroenterology Año: 2015 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos