• Keith C Olsen, Ramil E Sapinoro, R M Kottmann, Ajit A Kulkarni, Siiri E Iismaa, Gail V W Johnson, Thomas H Thatcher, Richard P Phipps, and Patricia J Sime.
• University of Rochester, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, NY 14642, USA.
• Am. J. Respir. Crit. Care Med.. 2011 Sep 15;184(6):699-707.

RationaleIdiopathic 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.ObjectivesTo determine the role of TG2 in pulmonary fibrosis.MethodsThe 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.Measurements And Main ResultsTG2 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.ConclusionsTG2 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.

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