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Expression of Transforming Growth Factor-β Induces Fibroproliferative Pulmonary Disease in Fibrosis-Resistant Mice*

Arnold R. Brody, PhD; G. Sakuntala Warshamana, PhD; , MD, PhD; Derek A. Pociask, PhD
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*From the Department of Pathology, Tulane University Health Sciences Center, New Orleans, LA.

Correspondence to: Arnold R. Brody, PhD, Professor and Vice Chair, Director, Lung Biology Program, Tulane University Health Sciences Center, 1430 Tulane Ave, New Orleans, LA 70112-2699



Chest. 2001;120(1_suppl):S48-S49. doi:10.1378/chest.120.1_suppl.S48-a
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While it appears that a number of growth factors must play an essential role in the development of fibroproliferative pulmonary disease, it is not known how each factor contributes to the various components that define the consequent interstitial fibrosis. We have been using transgenic and knockout mice to determine the roles of several of the growth factors. For example, mice with both receptors for tumor necrosis factor (TNF)-α knocked out are protected from the fibrogenic effects of asbestos1 and silica.2 Expression of transforming growth factor (TGF)-β1, platelet-derived growth factor, and TGF-α was clearly reduced in these knockout mice. Inasmuch as these mice failed to develop interstitial fibrosis after exposure to potent fibrogenic agents, we have now asked whether or not reconstitution of TGF-β1 expression through an adenovirus vector will induce fibroproliferative lung disease. Herein we report that transduction of the gene that codes for active TGF-β1 induces inflammation and a fibroproliferative process in the bronchiolar-alveolar regions of the lung in normal control mice as well as in the TNF-α receptor knockout mice (C57BL/6 X 129J, F2 generation). One-hundred million plaque-forming units (pfu) of replication-deficient adenovirus particles that expressed a porcine TGF-β1 gene were instilled into the lungs as described originally in a rat model.3 Vector alone caused slight perivascular lymphocyte accumulation. Under control of a cytomegalovirus promoter, the TGF-β1 gene was expressed rapidly, and active TGF-β1 protein was released causing interstitial inflammation and fibrogenesis during the first 7 days after instillation in the TNF-α receptor knockout mice. In addition, in C57BL/6 mice, large amounts of latent TGF-β1 were produced by the mice, as determined by enzyme-linked immunosorbent assay. The inflammation and fibrogenesis were documented by histopathology first at 4 days posttreatment and persisted through a 2-week period. Disease subsided, but the lungs had not returned to normal by the 4-week period studied in these experiments. A dose-response study was carried out in C57BL/6 mice, and a virus concentration of 106 pfu caused no apparent disease, whereas 109 pfu virus caused an overwhelming inflammatory response. At 108 pfu, BrdU incorporation showed 10-fold to 20-fold increases in cell proliferation. In conclusion, these findings demonstrate that expression of active TGF-β1 in the lungs of fibrosis-resistant TNF-α receptor knockout mice is sufficient to cause fibroproliferative pulmonary disease. The mechanisms through which TGF-β1 mediates collagen production and influences the expression of other cytokines are being investigated.

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