N Hagimoto, K Kuwano, H Miyazaki, R Kunitake, M Fujita, M Kawasaki, Y Kaneko and N Hara
Faculty of Medicine, Research Institute for Diseases of the Chest, Kyushu University, Higashiku, Fukuoka, Japan. hagimoto@j-pal.or.jp

Fas antigen is a cell surface protein that mediates apoptosis, and it is expressed in various cells and tissues. Fas ligand binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Malfunction of the Fas-Fas ligand system causes lymphoproliferative disorders and autoimmune diseases, whereas its exacerbation may cause tissue destruction. We hypothesize that excessive apoptosis mediated by Fas- Fas ligand interaction may damage alveolar epithelial cells and result in pulmonary fibrosis. Mice were allowed to inhale repeatedly an aerosolized anti-Fas antibody for 14 days. The nuclei of bronchial and alveolar epithelial cells were positively stained by in situ DNA nick end labeling. Electron microscopy demonstrated apoptotic changes in bronchial and alveolar epithelial cells. Histologic findings and hydroxyproline content showed the development of pulmonary fibrosis, which was dependent on the dose of anti-Fas antibody. The repeated inhalation of control antibody (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 antibody mimicking Fas-Fas ligand crosslinking induces excessive apoptosis and inflammation, which results in pulmonary fibrosis in mice.

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				A. N. Liu, A. Z. Mohammed, W. R. Rice, D. T. Fiedeldey, J. S. Liebermann, J. A. Whitsett, T. J. Braciale, and R. I. Enelow Perforin-Independent CD8+ T-Cell-Mediated Cytotoxicity of Alveolar Epithelial Cells Is Preferentially Mediated by Tumor Necrosis Factor-alpha . Relative Insensitivity to Fas Ligand Am. J. Respir. Cell Mol. Biol., May 1, 1999; 20(5): 849 - 858. [Abstract] [Full Text]

				R. Wang, A. Zagariya, O. Ibarra-Sunga, C. Gidea, E. Ang, S. Deshmukh, G. Chaudhary, J. Baraboutis, G. Filippatos, and B. D. Uhal Angiotensin II induces apoptosis in human and rat alveolar epithelial cells Am J Physiol Lung Cell Mol Physiol, May 1, 1999; 276(5): L885 - L889. [Abstract] [Full Text] [PDF]

				Y. Berthiaume, O. Lesur, and A. Dagenais Treatment of adult respiratory distress syndrome: plea for rescue therapy of the alveolar epithelium Thorax, February 1, 1999; 54(2): 150 - 160. [Full Text]

				K. Kuwano, H. Miyazaki, N. Hagimoto, M. Kawasaki, M. Fujita, R. Kunitake, Y. Kaneko, and N. Hara The Involvement of Fas-Fas Ligand Pathway in Fibrosing Lung Diseases Am. J. Respir. Cell Mol. Biol., January 1, 1999; 20(1): 53 - 60. [Abstract] [Full Text]

				N. Hussain, F. Wu, L. Zhu, R. S. Thrall, and M. J. Kresch Neutrophil Apoptosis during the Development and Resolution of Oleic Acid-Induced Acute Lung Injury in the Rat Am. J. Respir. Cell Mol. Biol., December 1, 1998; 19(6): 867 - 874. [Abstract] [Full Text]

				B. D. Uhal, I. Joshi, W. F. Hughes, C. Ramos, A. Pardo, and M. Selman Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung Am J Physiol Lung Cell Mol Physiol, December 1, 1998; 275(6): L1192 - L1199. [Abstract] [Full Text] [PDF]

				B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism Am J Physiol Lung Cell Mol Physiol, November 1, 1998; 275(5): L1013 - L1017. [Abstract] [Full Text] [PDF]

				C. Barazzone, S. Horowitz, Y. R. Donati, I. Rodriguez, and P.-F. Piguet Oxygen Toxicity in Mouse Lung: Pathways to Cell Death Am. J. Respir. Cell Mol. Biol., October 1, 1998; 19(4): 573 - 581. [Abstract] [Full Text]

				P. M. Yao and I. Tabas Free Cholesterol Loading of Macrophages Induces Apoptosis Involving the Fas Pathway J. Biol. Chem., July 28, 2000; 275(31): 23807 - 23813. [Abstract] [Full Text] [PDF]