title: Overexpression of tumor necrosis factor-alpha diminishes pulmonary fibrosis induced by bleomycin or transforming growth factor-beta.
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.
authors.affiliation: Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Fujita
authors.forename: John M
authors.initials: JM
authors.lastname: Shannon
authors.forename: Osamu
authors.initials: O
authors.lastname: Morikawa
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hara
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism*; D005822:Genetic Vectors; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D015232:Dinoprostone; D006909:Hydroxyproline