TNF-alpha receptor knockout mice are protected from the fibroproliferativeeffects of inhaled asbestos fibers

We have demonstrated that C57BL/6-129 hybrid mice with genes for both the 5 5kd and 75kd receptors for TNF-alpha knocked out (TNF-alpha RKO) fail to de velop fibroproliferative lesions after asbestos exposure. There is good evi dence that TNF-alpha plays a major role in mediating interstitial pulmonary fibrosis. Our findings support this view and we present here new data obta ined by in situ hybridization showing that expression of the genes coding f or 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 bromodeoxyur idine (BrdU) incorporation in the lungs of the TNF-alpha RKO mice show no i ncreases over unexposed control animals. in contrast, wild-type control mic e exposed to asbestos exhibit 15- to 20-fold increases in BrdU uptake and c onsequently develop fibrogenic lesions. Even though the levels of TNF-alpha gene expression and protein production were increased in the asbestos-expo sed TNF-alpha RKO mice, the lack of receptor signaling protected the mice f rom developing fibroproliferative lesions. We agree with the view that TNF- alpha is essential for the development of interstitial pulmonary fibrosis a nd postulate that TNF-alpha mediates its effects through activation of othe r growth factors such as PDGF and TGF-alpha that control cell growth and ma trix production.