Resistance of TNF/LT alpha double deficient mice to bleomycin-induced fibrosis.

In order to evaluate the role and mode of action of TNF in bleomycin-induced lung fibrosis, mice deficient for TNF and LT alpha (delta TNF/LT alpha) were examined at 2 months of age and after 3 weekly i.v. injections of bleomycin. The body weight of the delta TNF/LT alpha mice was 88 +/- 11% of that of the wild type littermates. Lung collagen, evaluated by its hydroxyproline content, was also lower (81 +/- 9%) in mutant than in wild type littermates. Bleomycin induced a diffuse alveolitis with focal areas of alveolar remodelling in wild type but not in delta TNF/LT alpha, mice. Lymphoid infiltration was also prominent in wild type, but absent from delta TNF/LT alpha, mice. Bleomycin injections increased collagen deposition, as evaluated by the lung hydroxyproline content, more markedly in wild type, than in delta TNF/LT alpha, mice. Cell trapping in the alveolar capillaries was evaluated by semi-quantitative electron microscopy. Bleomycin markedly increased platelet trapping in the alveolar capillaries of wild type, but not of delta TNF/LT alpha, mice. This study indicates that the expression of TNF/LT alpha genes increases the deposition of collagen in both untreated and inflamed lung and that these genes may act, at least in part, by promoting platelet trapping.