title: Complement Component 5 Mediates Development of Fibrosis, via Activation of Stellate Cells, in 2 Mouse Models of Chronic Pancreatitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Beyer
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Ujjwal M
authors.initials: UM
authors.lastname: Mahajan
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Vivien
authors.initials: V
authors.lastname: Kauschke
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Maertin
authors.affiliation: Interfaculty Institutes for Genetics and Functional Genomics, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schurmann
authors.affiliation: Interfaculty Institutes for Genetics and Functional Genomics, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Interfaculty Institutes for Genetics and Functional Genomics, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Institute for Community Medicine, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Halangk
authors.affiliation: Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wartmann
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Frank-Ulrich
authors.initials: FU
authors.lastname: Weiss
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary; MTA-SZTE Lendulet Translational Gastroenterology Research Group, Szeged, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Hegyi
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany. Electronic address: mayerle@uni-greifswald.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D016022:Case-Control Studies; D002108:Ceruletide; D003182:Complement C5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D008026:Ligation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010183:Pancreatic Ducts / Q000601:surgery; D058954:Pancreatic Stellate Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000814:Aniline Compounds; C000591759:C5ar1 protein, mouse; D003182:Complement C5; C470794:N-((4-dimethylaminophenyl)methyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide; D044087:Receptor, Anaphylatoxin C5a; D013764:Tetrahydronaphthalenes; D002108:Ceruletide
keywords: Complement System; Pancreatic Stellate Cells; Transcriptome Analysis; αSMA