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Overexpression of Tumor Necrosis Factor- Diminishes Pulmonary Fibrosis Induced by Bleomycin or Transforming Growth Factor-ß

Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado; Department of Pathology, University of McMaster, Hamilton, Ontario, Canada; and Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Address correspondence to: Robert J. Mason, M.D., Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: masonb{at}njc.org

Tumor necrosis factor- (TNF-) is thought to be important in the development of pulmonary fibrosis. However, surfactant protein-C/TNF- transgenic mice do not spontaneously develop pulmonary fibrosis but instead develop alveolar enlargement and loss of elastic recoil. We hypothesized that overexpression of TNF- in the lung requires an additional insult to produce fibrosis. In this study we evaluated whether TNF- overexpression altered the development of pulmonary fibrosis due to bleomycin or transforming growth factor-ß (TGF-ß). Either 0.2 U bleomycin or saline was administered into left lung of TNF- transgenic mice and their transgene-negative littermates. To overexpress TGF-ß, an adenovirus vector containing either active TGF-ß (AdTGF-ß) 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- transgenic mice tolerated bleomycin or AdTGF-ß, whereas the transgene-negative littermates demonstrated severe pulmonary fibrosis after either agent. An increase in prostaglandin E₂ and downregulation of TNF receptor I expression were observed in the TNF- transgenic mice. In addition, recombinant human TNF- attenuated bleomycin-induced pulmonary fibrosis. TNF- has a complex role in the development of pulmonary fibrosis. Endogenous TNF- may be important in the development of fibrosis as indicated in other reports, but overexpression of TNF- or exogenous TNF- limits pulmonary fibrosis in mice.

Abbreviations: LacZ adenovirus, AdLacZ • adenovirus vector of TGF-ß, AdTGF-ß • bronchoalveolar lavage, BAL • bleomycin, BLM • enzyme-linked immunosorbent assay, ELISA • idiopathic pulmonary fibrosis, IPF • matrix metalloproteinase, MMP • prostaglandin E₂, PGE₂ • recombinant tumor necrosis factor-, rTNF- • ribonuclease protection assay, RPA • surfactant protein C, SP-C • transforming growth factor-ß, TGF-ß • tumor necrosis factor-, TNF- • TNF receptor, TNFR