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Reduced Growth Factor Expression in Mice Resistant to Developing Fibroproliferative Lesions After Lung Injury* FREE TO VIEW

Arnold R. Brody, PhD; G. Hoyle; J.-Y. Liu; D. Brass
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*From the Lung Biology Program, Department of Pathology, Tulane University Medical Center, New Orleans, LA. Supported by NIH grants ES06766 and HL60532.

Correspondence to: Arnold R. Brody, PhD, Lung Biology Program, Tulane University Medical Center, 1430 Tulane Ave, New Orleans, LA 70112-2699

Chest. 1999;116(suppl_1):97S. doi:10.1378/chest.116.suppl_1.97S
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Following acute lung injury, there is proliferation of multiple cell types, including the alveolar epithelium, endothelium of small vessels, and interstitial fibroblasts. Our work has focused on the expression of selected genes and the cognate proteins that control cell proliferation and extracellular matrix production, the hallmarks of interstitial fibrogenesis. We are studying platelet-derived growth factor (PDGF), transforming growth factors alpha and beta (TGF-α, TGF-β), and tumor necrosis factor alpha (TNF-α). We have shown that these growth factors are expressed rapidly (within the first 5 to 24 h) after the initial alveolar injury caused by inhaled asbestos fibers.

Herein we present new data showing that two strains of mice are protected from the fibrogenic effects of inhaled asbestos fibers. One is an inbred, the 129 strain, and the second an F2 hybrid from a C57BL/6 (C57) and 129 cross (C57-129) that has had both the 55- and 75-kd receptors for TNF-α knocked out (C57-129KO). When these mice were exposed to an aerosol of chrysotile asbestos fibers for 5 h, they failed to develop fibroproliferative lesions at any time postexposure compared with the normal C57 and C57-129 mice. The 129 and C57-129KO mice had significantly reduced levels of bromodeoxyuridine incorporation, and most interestingly, levels of PDGF, TGF-β, and TGF-α expression clearly were diminished, as determined by in situ hybridization and immunohistochemistry. TNF-α expression was reduced in the 129 mice, but the gene and its protein remained at high levels in the C57-129KO animals. In addition, primary lung fibroblasts from 129 mice were maintained in culture and treated with varying concentrations of fetal bovine serum, PDGF, or TGF-β. Compared with a 3T3 fibroblast cell line and primary fibroblasts from C57 mice, cells from the 129 mice failed to proliferate in response to fetal bovine serum and PDGF, and they exhibited little type 1 procollagen gene expression after TGF-β treatment.

Based on these data, we postulate that TNF-α is playing a central role in mediating the fibroproliferative response consequent to lung injury. The C57-129KO mice generate substantial TNF-α, but they lack the receptors necessary to transduce the appropriate signals, as demonstrated by reduced growth factor expression and cell proliferation. The 129 mice have diminished growth factor expression, including TNF-α, and their fibroblasts appear to have an intrinsic lack of capacity to respond to fibroproliferative factors.




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