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Susceptibility to Asbestos-Induced and Transforming Growth Factor-ß₁–Induced Fibroproliferative Lung Disease in Two Strains of Mice

Lung Biology Program, Department of Pathology, Tulane University Health Sciences Center, New Orleans, Louisiana; Department of Medicine, University of Rochester, Rochester, New York; and Duke University Medical Center, Department of Medicine, Durham, North Carolina

Address correspondence to: Arnold R. Brody, Ph.D., Department of Pathology, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-79, New Orleans, LA 70112-2699. E-mail: abrody{at}tulane.edu

Pulmonary fibrosis (PF) is caused by a number of inhaled agents, as well as by some drugs and toxic particles. The elaboration of certain peptide growth factors is thought to be key to the development of this disease process. In addition, genetic susceptibility plays a role in the development of PF. For instance, we have previously shown that the 129J strain of mice is resistant, whereas the C57BL/6 strain is highly susceptible, to asbestos-induced fibrosis. To pursue this further, in one mouse model, we crossed the 129J strain to the C57BL/6 strain to produce an F1 generation and subsequently backcrossed the F1 mice to the inbred founders. This backcross to the 129 inbred strain produced 25% of the offspring with a phenotype that was protected from the fibrogenic effects of inhaled asbestos fibers. In the second model, both strains of mice were treated intratracheally with an adenovirus vector (AdV), which transduces expression of active transforming growth factor (TGF)-ß₁ in the lungs, producing fibroproliferative lung disease. Compared with C57 mice, a significant number of 129 strain mice exhibited at least a 1-wk delay in the fibroproliferative response to TGF-ß₁ expression at three concentrations of virus. These findings suggest that certain sequences in a gene or a cluster of genes in the 129 mouse strain impart a phenotype in which there is a delay in, or protection from, the development of lung fibrogenesis.

Abbreviations: adenovirus, AdV • bronchoalveolar lavage, BAL • Bromodeoxyuridine, BrdU • enzyme-linked immunosorbent assay, ELISA • hematoxylin and eosin, H&E • idiopathic pulmonary fibrosis, IPF • phosphate-buffered saline, PBS • platelet-derived growth factor, PDGF • pulmonary fibrosis, PF • plaque-forming units, pfu • transforming growth factor, TGF • tumor necrosis factor, TNF

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