Fas is a cell surface protein which transmits apoptosis signal to the cell, and Fas is recognized by Fas antibody (Yonehara, S. et al., J. Exp. Med., vol. 169, 1747-1756, 1989) which is a monoclonal antibody produced by immunizing a mouse with human fibroblast. Fas gene was recently cloned by Itoh, N. et al., and it was then found out that Fas is a cell membrane protein of about 45 kD, and from the amino acid sequence, it was revealed that Fas is a member of TNF receptor family (Cell, vol. 66, pages 233-243, 1991). Mouse Fas gene was also cloned (Watanabe-Fukunaga, R. et al., J. Immunol., vol. 148, pages 1274-1279, 1992), and the expression of Fas mRNA in thymus, liver, lung, heart, and ovary was confirmed.
Human Fas ligand is a polypeptide which has been reported by Negate et al. to be a biological molecule which induces apoptosis of Fas-expressing cells (Tomohiro Takahashi et al., International Immunology, vol. 6, pages 1567-1574, 1994). Human Fas ligand is a Type II glycoprotein of TNF family with a molecular weight of about 40 kD. As in the case of TNF, human Fas ligand in the human body is estimated to be in the form of a trimer (Masato Tanaka et al., EMBO Journal, vol. 14, pages 1129-1135, 1995). The extracellular domain of the human Fas ligand is highly homologous with the extracellular domain of rat Fas ligand (Takashi Suda et al., Cell, vol. 75, pages 1169-1178, 1993) and mouse Fas ligand (Tomohiro Takahashi et al., Cell, vol. 76, pages 969-976, 1994). The human Fas ligand recognizes not only the human Fas but also the mouse Fas to induce the apoptosis, and vice versa, the rat Fas ligand and the mouse Fas ligand also recognize the human Fas to induce the apoptosis.
Considerable researches have also been done on the mechanism of signal transduction in the cell upon the Fas-mediated apoptosis, and identification and cloning of the factor which interacts with the intracellular domain of the Fas, in particular, the region called “death domain” to transmit or block the signal have been reported. Possibility of the involvement of interleukin-1-converting enzyme (ICE)-related thiol proteases in the signal transduction of the Fas-mediated apoptosis has also been indicated.
Relationship of the apoptosis, in particular, the Fas-mediated apoptosis with various diseases and physiological phenomena has been recently indicated. For example, possibility has been indicated for involvement of abnormal Fas-mediated apoptosis in the death of hepatocytes in viral fulminant hepatitis, in some types of autoimmune diseases, and the like.
Involvement of the Fas/Fas ligand system in functions other than the apoptosis has also been indicated. For example, possibility has been indicated for the Fas/Fas ligand system to act with neutrophils to develop proinflammatory action (Kayagaki, N. et al., Rinshou Meneki (Clinical Immunology), vol. 28, pages 667-675, 1996).
Diffuse lung diseases are a group of diseases including interstitial pneumonia/pulmonary fibrosis and other diseases wherein the lesion expands in diffused manner. Such diseases may be etiologically categorized into cryptogenic diffuse lung diseases, diffuse lung diseases associated with collagen diseases, and phanerogenic diffuse lung diseases. Cryptogenic diffuse lung diseases include idiopathic interstitial pneumonia, and the like. Interstitial pneumonia/pulmonary fibrosis is a disease wherein lung inflammation invites reconstitution in the structure of alveoli and the resulting fibrotic change invites lung shrinkage and consolidation to threaten the life of the patient.
Cause of the fibrotic change of the lung has not been clearly found out. It has been, however, postulated that the fibrotic change of the lung is promoted by the mechanism wherein alveolus macrophage activated by immunocomplex induces accumulation and activation of neutrophils, and the thus induced secretion of cytotoxic oxidant, protease, and myeloperoxidase invites destruction of the pulmonary parenchyma. The alveolus macrophage that has been activated is also postulated to secrete a fibronectin and a growth factor, and the type I collagen secreted from the stimulated fibroblast precipitates in the lung to result in the fibrotic change of lung (Kudou, S., Naika (Internal Medicine), vol. 77, pp. 594-595, 1996; Kokyuki-byogaku (Respiratory Diseases), Oota, Y. et al. ed., Honma, Y. et al., pp. 48-63, 1990, Chugai-Igaku; Cantin, A. et al., Int. Archs Allergy Appl. Immun., vol. 76, suppl. 1, pp. 83-91, 1985).
In the case of the diffuse lung diseases, steroids are presently administered as a symptomatic treatment, and such steroid administration is recognized as a standard therapeutic method. The steroids, however, are well known for their side effects, and delicate care should be taken for the timing, dose and duration of the administration (Konnichi-no Chiryo-Shishin (Therapeutic Guide Today) 1997, Hinohara S. et al. ed.; Idiopathic Fibroid Lung, Nagai S., pp. 300-301, 1997).
An anti-tumor agent, bleomycin is known to be associated with a side effect, and diffuse alveoli disorder is induced in the acute phase and interstitial pneumonia/pulmonary fibrosis is induced in the chronic phase. Animal experiments have demonstrated that administration of bleomycin invites accelerated induction of inflammatory change, and correspondingly, enhanced increase of the fibroblasts and the extracellular matrix and the subsequent increase in the collagen concentration. The fibrotic change then gradually extends to interstitium, pleura, and the areas surrounding the bronchiole. In view of such situation, many investigations are conducted to model the human interstitial pneumonia/pulmonary fibrosis (Sato, S., Kokyu (Respiration), vol. 16, pp. 70-75, 1997).
The inventors of the present invention have reported that administration of the bleomycin into mouse lung by inhalation induces apoptosis of the bronchial and alveolar epithelial cells, as well as expression of Fas in the alveolar epithelial cells and Fas ligand in the infiltrated T cells (Am. J. Respir. Cell. Mol. Biol. vol. 16, pp. 91-101, 1997). The inventors of the present invention have also reported that apoptosis has been recognized in bronchial epithelium and alveolar epithelium in the case of the pulmonary fibrosis associated with idiopathic interstitial pneumonia or collagen diseases; that expression of Fas has been confirmed for bronchial epithelium and alveolar epithelium; and that expression of Fas ligand has been confirmed for the cells collected from bronchoalveolar lavage fluid (Program of 17th Meeting Japanese Society of Inflammations, p. 130, No. 16, 1996).
However, it has been still unknown whether the apoptosis mediated by the Eas and the Fas ligand is directly or indirectly involved in the pathology of the diffuse lung diseases, and no preventive and therapeutic agent for diffuse lung diseases has been known which acts by suppressing such apoptosis.