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Receptor Knockout Mice Are Protected from the Fibroproliferative Effects of Inhaled Asbestos Fibers
From the Lung Biology Program*
of the Department
of Pathology and the Department of Medicine,
Tulane University Medical Center, New Orleans, Louisiana
We have demonstrated that C57BL/6129 hybrid mice with
genes for both the 55kd and 75kd receptors for TNF-
knocked out
(TNF-
RKO) fail to develop fibroproliferative lesions after asbestos
exposure. There is good evidence that TNF-
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
(TGF-
) and platelet-derived growth
factor A-chain (PDGF-A) is reduced in the TNF-
RKO mice compared with
control animals. In accordance with this observation, data on
bromodeoxyuridine (BrdU) incorporation in the lungs of the TNF-
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-
gene expression
and protein production were increased in the asbestos-exposed
TNF-
RKO mice, the lack of receptor signaling protected the
mice from developing fibroproliferative lesions. We agree with the view
that TNF-
is essential for the development of interstitial pulmonary
fibrosis and postulate that TNF-
mediates its effects through
activation of other growth factors such as PDGF and TGF-
that
control cell growth and matrix production.
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