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Published ahead of print on June 19, 2003, doi:10.1165/rcmb.2002-0046OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 6, December 2003, 669-676

A more recent version of this article appeared on December 1, 2003
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Submitted on April 12, 2002
Revised on June 18, 2003

Overexpression of TNF-alpha diminishes pulmonary fibrosis induced by bleomycin or TGF-beta

Masaki Fujita1, John M Shannon1, Osamu Morikawa1, Jack Gauldie2, Nobuyuki Hara3, and Robert J Mason1*

1 Department of Medicine, National Jewish Medical and Research Center, Denver, CO, USA, 2 Department of Pathology, University of McMaster, Ontario, Canada, 3 Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

* To whom correspondence should be addressed. E-mail: masonb{at}njc.org.

Tumor necrosis factor alpha (TNF-{alpha}) is thought to be important in the development of pulmonary fibrosis. However, SP-C/TNF-{alpha} transgenic mice do not spontaneously develop pulmonary fibrosis but instead develop alveolar enlargement and loss of elastic recoil. We hypothesized that overexpression of TNF-{alpha} in the lung requires an additional insult to produce fibrosis. In this study we evaluated whether TNF-{alpha} overexpression altered the development of pulmonary fibrosis due to bleomycin or transforming growth factor beta (TGF-{beta}). Either 0.2 units of bleomycin or saline was administered into left lung of TNF-{alpha} transgenic mice and their transgene-negative littermates. To overexpress TGF-{beta}, an adenovirus vector containing either TGF-{beta} (AdTGF-{beta}) or LacZ was administered at a dose of 3 x 108 plaque forming units per mouse. Fibrosis was assessed histologically and by measurement of hydroxyproline. TNF-{alpha} transgenic mice tolerated bleomycin or AdTGF-{beta}, whereas the transgene-negative littermates demonstrated severe pulmonary fibrosis after either bleomycin or AdTGF-{beta}. An increase in PGE2 and down-regulation of TNF receptor I expression were observed in the TNF-{alpha} transgenic mice. In addition, recombinant human TNF-{alpha} attenuated bleomycin-induced pulmonary fibrosis. TNF-{alpha} has a complex role in the development of pulmonary fibrosis. Endogenous TNF-{alpha} may be important in the development of fibrosis as indicated in other reports, but overexpression of TNF-{alpha} or exogenous TNF-{alpha} limits pulmonary fibrosis in mice.




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