Conditional expression of transforming growth factor-alpha in adult mouse lung causes pulmonary fibrosis.
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.
Hardie
William D
WD
Div. of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA. william.hardie@cchmc.org
Le Cras
Timothy D
TD
Jiang
Kenny
K
Tichelaar
Jay W
JW
Azhar
Mohamad
M
Korfhagen
Thomas R
TR
D000367:Age Factors; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002455:Cell Division; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics
D000900:Anti-Bacterial Agents; D016326:Extracellular Matrix Proteins; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D003094:Collagen; D004318:Doxycycline