Article

Overexpression of tumor necrosis factor-alpha diminishes pulmonary fibrosis induced by bleomycin or transforming growth factor-beta.

Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
American Journal of Respiratory Cell and Molecular Biology (impact factor: 5.13). 01/2004; 29(6):669-76. DOI:10.1165/rcmb.2002-0046OC pp.669-76
Source: PubMed

ABSTRACT Tumor necrosis factor-alpha (TNF-alpha) is thought to be important in the development of pulmonary fibrosis. However, surfactant protein-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 U 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 active 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 agent. An increase in prostaglandin E2 and downregulation 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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Keywords

3 x 108 plaque-forming units
 
active TGF-beta
 
adenovirus vector
 
AdTGF-beta
 
alveolar enlargement
 
downregulation
 
elastic recoil
 
Endogenous TNF-alpha
 
exogenous TNF-alpha limits pulmonary fibrosis
 
growth factor-beta
 
overexpress TGF-beta
 
prostaglandin E2
 
pulmonary fibrosis
 
severe pulmonary fibrosis
 
surfactant protein-C/TNF-alpha transgenic mice
 
TNF receptor
 
TNF-alpha overexpression
 
TNF-alpha transgenic mice
 
Tumor necrosis factor-alpha
 
U bleomycin