Resistance of TNF/LTα double deficient mice to bleomycin-induced fibrosis


Pierre F. Piguet Department of Pathology, University of Geneva, Geneva 1211, Switzerland


In order to evaluate the role and mode of action of TNF in bleomycin-induced lung fibrosis, mice deficient for TNF and LTα (ΔTNF/LTα) were examined at 2 months of age and after 3 weekly i.v. injections of bleomycin. The body weight of the ΔTNF/LTα 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 ΔTNF/LTα, mice. Lymphoid infiltration was also prominent in wild type, but absent from ΔTNF/LTα, mice. Bleomycin injections increased collagen deposition, as evaluated by the lung hydroxyproline content, more markedly in wild type, than in ΔTNF/LTα, 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 ΔTNF/LTα, mice. This study indicates that the expression of TNF/LTα 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.