title: Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism.
abstract: Coagulation cascade activation and fibrin deposits have been implicated or observed in diverse forms of liver damage. Given that fibrin amplifies pathological inflammation in several diseases through the integrin receptor αMβ2, we tested the hypothesis that disruption of the fibrin(ogen)-αMβ2 interaction in Fibγ(390-396A) mice would reduce hepatic inflammation and fibrosis in an experimental setting of chemical liver injury. Contrary to our hypothesis, α-naphthylisothiocyanate (ANIT)-induced liver fibrosis increased in Fibγ(390-396A) mice, whereas inflammatory cytokine expression and hepatic necrosis were similar to ANIT-challenged wild-type (WT) mice. Increased fibrosis in Fibγ(390-396A) mice appeared to be independent of coagulation factor 13 (FXIII) transglutaminase, as ANIT challenge in FXIII-deficient mice resulted in a distinct pathological phenotype characterized by increased hepatic necrosis. Rather, bile duct proliferation underpinned the increased fibrosis in ANIT-exposed Fibγ(390-396A) mice. The mechanism of fibrin-mediated fibrosis was linked to interferon (IFN)γ induction of inducible nitric oxide synthase (iNOS), a gene linked to bile duct hyperplasia and liver fibrosis. Expression of iNOS messenger RNA was significantly increased in livers of ANIT-exposed Fibγ(390-396A) mice. Fibrin(ogen)-αMβ2 interaction inhibited iNOS induction in macrophages stimulated with IFNγ in vitro and ANIT-challenged IFNγ-deficient mice had reduced iNOS induction, bile duct hyperplasia, and liver fibrosis. Further, ANIT-induced iNOS expression, liver fibrosis, and bile duct hyperplasia were significantly reduced in WT mice administered leukadherin-1, a small molecule that allosterically enhances αMβ2-dependent cell adhesion to fibrin. These studies characterize a novel mechanism whereby the fibrin(ogen)-integrin-αMβ2 interaction reduces biliary fibrosis and suggests a novel putative therapeutic target for this difficult-to-treat fibrotic disease.
authors.affiliation: Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, and.
authors.forename: Nikita
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Institute for Integrative Toxicology, and Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI;
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kopec
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI;
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Ray
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI;
authors.forename: Holly
authors.initials: H
authors.lastname: Cline-Fedewa
authors.affiliation: Department of Surgery, The University of Kansas Medical Center, Kansas City, KS;
authors.forename: Atta
authors.initials: A
authors.lastname: Nawabi
authors.affiliation: Department of Surgery, The University of Kansas Medical Center, Kansas City, KS;
authors.forename: Timothy
authors.initials: T
authors.lastname: Schmitt
authors.affiliation: Institute for Integrative Toxicology, and Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI; and.
authors.forename: Rance
authors.initials: R
authors.lastname: Nault
authors.affiliation: Institute for Integrative Toxicology, and Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI; and.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Zacharewski
authors.affiliation: Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, and.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Rockwell
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.affiliation: Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, and Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI;
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001652:Bile Ducts / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D005260:Female; D005337:Fibrin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D013867:Thiohydantoins / Q000494:pharmacology
chemical_list: D001565:Benzoates; C573415:IFNG protein, human; C000611649:IFNG protein, mouse; D016177:Macrophage-1 Antigen; D013867:Thiohydantoins; C000589733:leukadherin-1; D015058:1-Naphthylisothiocyanate; D007371:Interferon-gamma; D005337:Fibrin