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Am J Physiol Lung Cell Mol Physiol 286: L741-L749, 2004. First published December 5, 2003; doi:10.1152/ajplung.00208.2003
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Conditional expression of transforming growth factor-{alpha} in adult mouse lung causes pulmonary fibrosis

William D. Hardie,1 Timothy D. Le Cras,2 Kenny Jiang,1 Jay W. Tichelaar,3 Mohamad Azhar,4 and Thomas R. Korfhagen2

Divisions of 1Pulmonary Medicine and 2Pulmonary Biology, Children's Hospital Medical Center, Cincinnati 45229-3039; and 3Department of Environmental Health, Division of Toxicology, 4Division of Molecular Genetics, University of Cincinnati, Cincinnati, Ohio 45267-0056

Submitted 30 June 2003 ; accepted in final form 26 November 2003

To determine whether overexpression of transforming growth factor (TGF)-{alpha} in the adult lung causes remodeling independently of developmental influences, we generated conditional transgenic mice expressing TGF-{alpha} in the epithelium under control of the doxycycline (Dox)-regulatable Clara cell secretory protein promoter. Two transgenic lines were generated, and following 4 days of Dox-induction TGF-{alpha} levels in whole lung homogenate were increased 13- to 18-fold above nontransgenic levels. After TGF-{alpha} induction, transgenic mice developed progressive pulmonary fibrosis and body weight loss, with mice losing 15% of their weight after 6 wk of TGF-{alpha} induction. Fibrosis was detected within 4 days of TGF-{alpha} induction and developed initially in the perivascular, peribronchial, and pleural regions but later extended into the interstitium. Fibrotic regions were composed of increased collagen and cellular proliferation and were adjacent to airway and alveolar epithelial sites of TGF-{alpha} expression. Fibrosis progressed in the absence of inflammatory cell infiltrates as determined by histology, without changes in bronchiolar alveolar lavage total or differential cell counts and without changes in proinflammatory cytokines TNF-{alpha} or IL-6. Active TGF-{beta} in whole lung homogenate was not altered 1 and 4 days after TGF-{alpha} induction, and immunostaining was not increased in the peribronchial/perivascular areas at all time points. Chronic epithelial expression of TGF-{alpha} in adult mice caused progressive pulmonary fibrosis associated with increased collagen and extracellular matrix deposition and increased cellular proliferation. Induction of pulmonary fibrosis by TGF-{alpha} was independent of inflammation or early activation of TGF-{beta}.

collagen; proliferation; epidermal growth factor receptor; transforming growth factor-{beta}


Address for reprint requests and other correspondence: W. D. Hardie, Div. of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (E-mail: william.hardie{at}cchmc.org).




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