INDUCTION OF APOPTOSIS AND PULMONARY FIBROSIS IN MICE IN RESPONSE TO LIGATION OF FAS ANTIGEN

Fas antigen is a cell surface protein that mediates apoptosis, and it is expressed in various cells and tissues. Fas ligand binds to its rec eptor Fas, thus inducing apoptosis of Fas-bearing cells. Malfunction o f the Fas-Fas ligand system causes lymphoproliferative disorders and a utoimmune diseases, whereas its exacerbation may cause tissue destruct ion. We hypothesize that excessive apoptosis mediated by Fas-Fas ligan d interaction may damage alveolar epithelial cells and result in pulmo nary fibrosis. Mice were allowed to inhale repeatedly an aerosolized a nti-Ws antibody for 14 days. The nuclei of bronchial and alveolar epit helial cells were positively stained by in situ DNA nick end labeling. Electron microscopy demonstrated apoptotic changes in bronchial and a lveolar epithelial cells. Histologic findings and hydroxyproline conte nt showed the development of pulmonary fibrosis, which was dependent o n the dose of anti-Fas antibody. The repeated inhalation of control an tibody (isotype-matched control hamster IgG) did not induce apoptosis of epithelial cells or pulmonary fibrosis. The expression of TGF-beta mRNA was upregulated from day 7 to day 28 in lung tissues of anti-Fas antibody-treated mice but not in those of control mice. In this report , we present the evidence that repeated inhalation of anti-Fas antibod y mimicking Fas-Fas ligand cross-linking induces excessive apoptosis a nd inflammation, which results in pulmonary fibrosis in mice.