Conditional expression of transforming growth factor-alpha in adult mouse lung causes pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2004 Apr;286(4):L741-9
Date
12/09/2003Pubmed ID
14660483DOI
10.1152/ajplung.00208.2003Scopus ID
2-s2.0-1642269164 (requires institutional sign-in at Scopus site) 98 CitationsAbstract
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.
Author List
Hardie WD, Le Cras TD, Jiang K, Tichelaar JW, Azhar M, Korfhagen TRMESH terms used to index this publication - Major topics in bold
Age FactorsAnimals
Anti-Bacterial Agents
Cell Division
Collagen
Disease Progression
Doxycycline
Extracellular Matrix Proteins
Gene Expression
Mice
Mice, Transgenic
Pneumonia
Pulmonary Fibrosis
Transforming Growth Factor alpha
Transforming Growth Factor beta
