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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{at}tulane.edu
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-ß and platelet-derived
growth factor-
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 x 129 (score,
1.5 ± 0.75; n = 19) vs F1 x 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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and transforming growth factor-ß1 expression in the lungs of inbred mice that fail to develop fibroproliferative lesions consequent to asbestos exposure. Am J Pathol 154,853-862This article has been cited by other articles:
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  T. Sabo-Attwood, M. Ramos-Nino, J. Bond, K. J. Butnor, N. Heintz, A. D. Gruber, C. Steele, D. J. Taatjes, P. Vacek, and B. T. Mossman Gene Expression Profiles Reveal Increased mClca3 (Gob5) Expression and Mucin Production in a Murine Model of Asbestos-Induced Fibrogenesis Am. J. Pathol., November 1, 2005; 167(5): 1243 - 1256. [Abstract] [Full Text] [PDF]
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