title: Transglutaminase 2 and its role in pulmonary fibrosis.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a deadly progressive disease with few treatment options. Transglutaminase 2 (TG2) is a multifunctional protein, but its function in pulmonary fibrosis is unknown.
  
  
  OBJECTIVE
  To determine the role of TG2 in pulmonary fibrosis.
  
  
  METHODS
  The fibrotic response to bleomycin was compared between wild-type and TG2 knockout mice. Transglutaminase and transglutaminase-catalyzed isopeptide bond expression was examined in formalin-fixed human lung biopsy sections by immunohistochemistry from patients with IPF. In addition, primary human lung fibroblasts were used to study TG2 function in vitro.
  
  
  RESULTS
  TG2 knockout mice developed significantly reduced fibrosis compared with wild-type mice as determined by hydroxyproline content and histologic fibrosis score (P < 0.05). TG2 expression and activity are increased in lung biopsy sections in humans with IPF compared with normal control subjects. In vitro overexpression of TG2 led to increased fibronectin deposition, whereas transglutaminase knockdown led to defects in contraction and adhesion. The profibrotic cytokine transforming growth factor-β causes an increase in membrane-localized TG2, increasing its enzymatic activity.
  
  
  CONCLUSIONS
  TG2 is involved in pulmonary fibrosis in a mouse model and in human disease and is important in normal fibroblast function. With continued research on TG2, it may offer a new therapeutic target.
authors.affiliation: University of Rochester, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, NY 14642, USA.
authors.forename: Keith C
authors.initials: KC
authors.lastname: Olsen
authors.forename: Ramil E
authors.initials: RE
authors.lastname: Sapinoro
authors.forename: R M
authors.initials: RM
authors.lastname: Kottmann
authors.forename: Ajit A
authors.initials: AA
authors.lastname: Kulkarni
authors.forename: Siiri E
authors.initials: SE
authors.lastname: Iismaa
authors.forename: Gail V W
authors.initials: GV
authors.lastname: Johnson
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000201:enzymology; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000201:enzymology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011658:Pulmonary Fibrosis / Q000201:enzymology*; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins