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Identifying Fibrosis Susceptibility Genes in Two Strains of Inbred Mice*

Arnold R. Brody, PhD; G. Sakuntala Warshamana, PhD; Jing-Yao Liu, MD; Shang-Yi Tsai; Derek A. Pociask, PhD; David M. Brass; David Schwartz, MD, FCCP
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*From the Lung Biology Program (Drs. Brody, Warshamana, Liu, Tsai, and Pociask), Tulane University Health Sciences Center, New Orleans, LA, and the Department of Medicine (Drs. Brass and Schwartz), Duke University Medical Center, Durham, NC.

Correspondence to: Arnold R. Brody, PhD, School of Medicine, Department of Pathology and Laboratory Medicine, SL79, 1430 Tulane Ave, New Orleans, LA 70112-2699; e-mail: abrody@tulane.edu



Chest. 2002;121(3_suppl):31S. doi:10.1378/chest.121.3_suppl.31S
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The 129-J (129) and C57BL/6 (C57) strains of mice are commonly used in models of lung disease. These mice also are used to generate gene knockouts and transgenic mouse models. We have previously demonstrated that the 129 strain exhibits a reduced fibroproliferative response to inhaled asbestos,1 compared to the C57 mice that develop clear fibrogenic foci at sites of lung injury. Primary lung fibroblasts obtained from the 129 strain also exhibit reduced growth responses to platelet-derived growth factor and serum, and the cells have reduced expression of transforming growth factor-β and platelet-derived growth factor-α receptor in culture. We report here our experiments designed to identify a gene or complex of genes that mediate these two clearly identified phenotypes in vivo. The experiments were carried out on the two inbred founder strains (129, C57), on an F1 intercross between these two strains and on backcross progeny between the F1s and either the 129 or C57 inbred founders. The study progressed in two phases: (1) blinded histopathologic scoring of asbestos-exposed (48 h after two 5-h exposures) and unexposed control mice, and (2) microarray analysis of whole-lung messenger RNA from selected exposed and control mice. The histopathology scores ranged from 0 (normal) to 4 (diffuse interstitial fibrogenesis). The average (± SD) score for all strains of unexposed mice was 0.5 ± 1.0 (n = 16). The score for asbestos-exposed 129 mice was 1.8 ± 0.7 (n = 5), and the exposed C57 mice were significantly greater (p < 0.001) at 2.7 ± 0.8 (n = 10). The F2 generation yielded highly significant differences (p < 0.0005) between the F1 × 129 (score, 1.5 ± 0.75; n = 19) vs F1 × C57 (score, 2.4 ± 0.65; n = 21) backcrosses. Histopathologic analysis of the F1 generation of progeny yielded a bell-shaped curve of scores from 0 to 3. Messenger RNAs from the lungs of the founders, F1 generation, and F2 backcrosses (exposed and unexposed) were subjected to hybridization by microarray. RNAs from low and high responders in each group are currently being compared. Results from the microarray analysis are just now becoming available and will be analyzed by appropriate statistical tests. The first data set is anticipated by the end of February, 2001, and repeat analyses should be available by April or May.

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