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(American Journal of Pathology. 1998;153:1839-1847.)
© 1998 American Society for Investigative Pathology


Regular Articles

TNF-{alpha} Receptor Knockout Mice Are Protected from the Fibroproliferative Effects of Inhaled Asbestos Fibers

Jing-Yao Liu* , David M. Brass* , Gary W. Hoyle{dagger} and Arnold R. Brody*

From the Lung Biology Program* of the Department of Pathology and the Department of Medicine,{dagger} Tulane University Medical Center, New Orleans, Louisiana

We have demonstrated that C57BL/6–129 hybrid mice with genes for both the 55kd and 75kd receptors for TNF-{alpha} knocked out (TNF-{alpha}RKO) fail to develop fibroproliferative lesions after asbestos exposure. There is good evidence that TNF-{alpha} plays a major role in mediating interstitial pulmonary fibrosis. Our findings support this view and we present here new data obtained by in situ hybridization showing that expression of the genes coding for transforming growth factor {alpha} (TGF-{alpha}) and platelet-derived growth factor A-chain (PDGF-A) is reduced in the TNF-{alpha}RKO mice compared with control animals. In accordance with this observation, data on bromodeoxyuridine (BrdU) incorporation in the lungs of the TNF-{alpha}RKO mice show no increases over unexposed control animals. In contrast, wild-type control mice exposed to asbestos exhibit 15- to 20-fold increases in BrdU uptake and consequently develop fibrogenic lesions. Even though the levels of TNF-{alpha} gene expression and protein production were increased in the asbestos-exposed TNF-{alpha}RKO mice, the lack of receptor signaling protected the mice from developing fibroproliferative lesions. We agree with the view that TNF-{alpha} is essential for the development of interstitial pulmonary fibrosis and postulate that TNF-{alpha} mediates its effects through activation of other growth factors such as PDGF and TGF-{alpha} that control cell growth and matrix production.





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