Tumor necrosis factor plays an essential role in determining hypersensitivity pneumonitis in a mouse model.
We examined the importance of the cytokine tumor necrosis factor-alpha (TNF-alpha) in a mouse model of hypersensitivity pneumonitis (HP). Mice of the C57BL/6 strain were instilled intranasally 3 days/wk for 3 wk with 150 micrograms of the actinomycete Faenia rectivirgula (Micropolyspora faeni) to induce HP as a model of farmer's lung. This experimental model was associated with a progressive inflammation in the lungs of challenged mice, seen histologically as cellular infiltrates of large quantities of macrophages and lymphocytes and some neutrophils. The disease in challenged mice treated with a control rabbit serum was also associated with a substantial release of tumor TNF-alpha (up to 80 U/ml of TNF-alpha in the bronchoalveolar lavage [BAL] at 3 wk after beginning of treatment) and interleukin-1, which peaked at 1 wk (approximately 300 U/ml) and diminished thereafter. A very large increase in BAL cell number (11-fold increase versus saline controls) and an enhanced release potential for TNF-alpha by alveolar macrophages was also seen. Lung fibrosis was also evident in challenged animals, as demonstrated by a 2-fold increase in hydroxyproline levels. Infusion of challenged mice with a rabbit polyclonal antibody against TNF-alpha (2 mg/wk) completely abrogated the disease, as mice so treated had normal lung histology. Anti-TNF-alpha blocked cellular recruitment in the lungs (only a 2-fold increase at week 3); it also completely abolished TNF-alpha secretion in the BAL and drastically reduced interleukin-1 levels in this fluid. Anti-TNF-alpha also abolished lung index increases and lung fibrosis, with both parameters similar to that of saline-instilled mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Denis
M
M
Unité de recherche, Centre de Pneumologie, Hôpital Laval, Sainte-Foy, Quebec, Canada.
Cormier
Y
Y
Fournier
M
M
Tardif
J
J
Laviolette
M
M
D000542:Alveolitis, Extrinsic Allergic / Q000209:etiology* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D007106:Immune Sera; D007700:Kinetics; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016930:Saccharopolyspora / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*
D007106:Immune Sera; D014409:Tumor Necrosis Factor-alpha