Biomedical subjects

T Maeyama

Publications and source records attributed to T Maeyama.

At least 19 recordsLinked to original sources

PubMed2005

The p53-Mdm2 association in epithelial cells in idiopathic pulmonary fibrosis and non-specific interstitial pneumonia.

BACKGROUND: Wild-type p53 is increased during cellular responses to various stresses. Mdm2, which is induced by p53, regulates p53 protein concentrations through the ubiquitin-proteasome pathway. AIM: To investigate whether the Mdm2 mediated ubiquitination of p53 is associated with epithelial cell apoptosis in idiopathic pulmonary fibrosis (IPF). METHODS: Immunohistochemistry and western blot analysis were carried out on lung samples obtained by lung biopsy from patients with IPF and non-specific interstitial pneumonia (NSIP). RESULTS: The expression of p53, phosphorylated p53, Mdm2, p21, and Bax was upregulated in epithelial cells from patients with IPF and NSIP compared with normal lung parenchyma. Except for p21, there was a significant increase in the expression of these factors in IPF compared with NSIP. In addition, the number of apoptotic cells and the number of p53 and Bax positive cells was increased compared with controls. p53 conjugated with Mdm2 was decreased in IPF compared with NSIP and controls. Ubiquitinated p53 was increased in both IPF and NSIP compared with controls. CONCLUSIONS: Signalling molecules associated with p53 mediated apoptosis may participate in epithelial cell apoptosis, and the attenuation of p53-Mdm2 conjugation and of p53 degradation may be involved in the epithelial cell apoptosis seen in IPF. Augmented epithelial apoptosis in IPF may lead to the poor prognosis compared with NSIP.

Adult↗

PubMed2005

Apoptosis signaling pathways in lung diseases.

Evidence that apoptosis plays an important role in the pathophysiology of lung diseases has been accumulated. Apoptosis signaling is classically composed of two principle pathways. One is a direct pathway from death receptor ligation to caspase cascade activation and cell death. Death receptor ligation triggers recruitment of the precursor form of caspase-8 to a death-inducing complex, through the adaptor protein FADD, which leads to caspase-8 activation. The other pathway triggered by stimuli such as drugs, radiation, infectious agents and reactive oxygen species is initiated in mitochondria. After cytochrome c is released into the cytosol from the mitochondria, it binds to Apaf1 and ATP, which then activate caspase-9. Recently, endoplasmic reticulum has also been shown to be the organelle to execute apoptosis. Further understanding of molecular mechanisms of apoptosis and its regulation by novel drugs may lead to the development of effective strategies against lung diseases. We overview the signaling pathways of apoptosis and discuss the involvement of apoptosis in the pathophysiology of various lung diseases.

Animals↗

PubMed2004

The perforin mediated apoptotic pathway in lung injury and fibrosis.

AIMS: The perforin mediated pathway is the major pathway of cytotoxicity induced by activated T cells and natural killer cells, and may be involved in the development of pulmonary fibrosis. METHODS: Perforin and granzyme B expression were examined in idiopathic pulmonary fibrosis by means of immunohistochemistry, and perforin knockout mice were used to examine whether or not perforin mediated cytotoxicity participates in the pathophysiology of bleomycin induced pneumopathy. RESULTS: Perforin and granzyme B expression were upregulated in infiltrating lymphocytes in lung tissue from patients with idiopathic pulmonary fibrosis compared with normal lung parenchyma. Perforin and granzyme B expression were upregulated predominantly in infiltrating mononuclear cells after bleomycin instillation in wild-type mice. Although the development of bleomycin induced pneumopathy was not completely prevented, the pathological grade of inflammation and fibrosis, and the number of apoptotic cells in lung tissue, were significantly decreased in perforin knockout mice compared with wild-type mice. CONCLUSIONS: These results suggest that perforin mediated apoptosis may be associated with the pathophysiology of lung injury and fibrosis.

Animals↗

PubMed2003

Oxidative stress in lung epithelial cells from patients with idiopathic interstitial pneumonias.

Lung epithelial cells are a primary target for reactive oxygen species (ROS). ROS can cause oxidative deoxyribonucleic acid modification, such as 8-hydroxy-deoxyguanosine (8-OHdG). A human homologue of the MutT protein (hMTH1) prevents this modification. Mitochondria are the most important cellular source of ROS and may be susceptible to oxidative damage. The purpose of this study is to investigate oxidative stress and mitochondrial damage in lung epithelial cells from idiopathic interstitial pneumonias (IIPs). The authors analysed 8-OHdG, hMTH1, and mitochondrial proteins on lung specimens from 13 patients with IlPs consisted of eight patients with usual interstitial pneumonia and five patients with nonspecific interstitial pneumonia using Western blot analysis and immunohistochemistry. Immunoreactivity for 8-OHdG and hMTH1 was significantly increased in the lung epithelial cells from patients with IIPs compared with controls. The expression of hMTH1 was localised in the nuclear and cytoplasmic, but not the mitochondrial, fraction of lung homogenates. Immunoreactivity for mitochondrial protein and cytochrome c oxidase complex subunit IV was increased in the lung epithelial cells from patients with IIPs compared with controls. The current study concludes that oxidative stress may participate in epithelial cell damage in idiopathic interstitial pneumonia, and that increased mitochondrial mass may associate with increased reactive oxygen species production in idiopathic interstitial pneumonia.

Blotting, Western↗

PubMed2002

Resistance to Fas-mediated apoptosis in human lung fibroblast.

The current authors have demonstrated previously that epithelial cell apoptosis, induced by the Fas-Fas ligand pathway, might be involved in fibrosing lung diseases. Whereas lung epithelial cells are sensitive to the Fas-mediated apoptosis, lung fibroblasts may be resistant to Fas-mediated apoptosis and replace damaged epithelial cells. The WI-38 lung fibroblast cell line and primary lung fibroblasts were used to examine the resistant to Fas-mediated apoptosis and the association of anti-apoptotic proteins with this resistance. The administration of agonistic anti-Fas antibody (CH-11) or cycloheximide alone did not induce apoptosis, whereas the co-administration of CH-11 with cycloheximide induced apoptosis in WI-38 cells, in which caspase-8 and -3, but not -9, were activated, and X chromosome-linked inhibitor of apoptosis (ILP) and FLICE-like inhibitor protein (FLIP(L)), but not bcl-xL and bcl-2, were remarkably down regulated. Primary lung fibroblasts were also resistant to Fas-mediated apoptosis, and ILP and FLIP appeared to be involved in this resistance. Furthermore, the results of immunohistochemistry demonstrated that fibroblasts expressed ILP and FLIP(L) proteins in lung tissues from patients with idiopathic pulmonary fibrosis. These results suggest that anti-apoptotic proteins such as X chromosome-linked inhibitor of apoptosis and FLICE-like inhibitor protein may play an important role in preventing Fas-mediated apoptosis in lung fibroblasts, and participate in the development of pulmonary fibrosis.

Adult↗

PubMed2001

Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor.

Caspases have been implicated in the effector process of apoptosis in several systems including the Fas-Fas ligand pathway. We previously demonstrated that excessive apoptosis of lung epithelial cells and the Fas-Fas ligand pathway were essential in the pathogenesis of bleomycin-induced pneumopathy in mice. Therefore, the purpose of this study was to investigate whether a caspase inhibitor could prevent the development of this model. The expression of caspase-1 and caspase-3 was upregulated on lung epithelial cells, alveolar macrophages, and infiltrating inflammatory cells in this model. We demonstrated that a broad-spectrum caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, decreased the caspase-1- and caspase-3-like activity, the number of apoptotic cells, the pathological grade of lung inflammation and fibrosis, and the hydroxyproline content in lung tissues in this model. We conclude that caspase inhibitors could be a new therapeutic approach against lung injury and pulmonary fibrosis.

Administration, Inhalation↗

PubMed2001

Attenuation of bleomycin-induced pneumopathy in mice by monoclonal antibody to interleukin-12.

We previously demonstrated essential roles of the Fas-Fas ligand (FasL) pathway in bleomycin-induced pneumopathy in mice. T lymphocytes and natural killer cells express FasL on activation and use it as a cytotoxic effector molecule. Because interleukin (IL)-12 is known to play a critical role in cell-mediated immunity, we investigated whether anti-IL-12 antibody treatment suppresses the development of this model. The anti-IL-12 antibody treatment decreased the number of apoptotic cells and the degree of inflammation and fibrosis in lung tissue. The results of RT-PCR showed that IL-12p40, IL-12 receptor (R) beta2, interferon-gamma, tumor necrosis factor-alpha and FasL mRNAs were upregulated after bleomycin instillation. The upregulation of FasL, IL-12Rbeta2, and tumor necrosis factor-alpha mRNA expression in lung tissue was suppressed by anti-IL-12 antibody treatment. The results of enzyme-linked immunosorbent assay showed that the levels of IL-12p40, but not of IL-12p70, were increased in lung tissue after bleomycin instillation. Although the increase in IL-12Rbeta2 mRNA levels suggests that the T helper type 1 cell response may participate in lung injury, the increase in IL-12p40 supports T helper type 2 cell predominance in the fibrotic process of this model. The administration of anti-IL-12 antibody could be a novel therapy against lung injury and pulmonary fibrosis.

Animals↗

PubMed2001

KL-6, surfactant protein A and D in bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis.

BACKGROUND: KL-6, and surfactant protein A (SP-A) and surfactant protein D (SP-D) derived from alveolar type II cells and/or bronchiolar epithelial cells have been reported to be useful markers for interstitial lung diseases. OBJECTIVE: The aim of this study was to measure the levels of these molecules in bronchoalveolar lavage fluid (BALF) from patients with pulmonary sarcoidosis to investigate their relationship with other markers of inflammatory activity. METHODS: We measured KL-6, SP-A and SP-D levels in BALF from patients with pulmonary sarcoidosis using an ELISA. RESULTS: KL-6 and SP-D, but not SP-A levels were significantly increased in pulmonary sarcoidosis compared with controls. KL-6, SP-A and SP-D levels were significantly correlated with each other. KL-6 and SP-D levels were relatively and significantly correlated with the percentage of lymphocytes in BALF. KL-6, SP-D, but not SP-A levels were significantly correlated with the concentration of albumin in BALF. There was no significant correlation between KL-6, SP-A, or SP-D levels and chest X-ray findings, angiotensin-converting enzyme levels, or CD4/CD8 ratio in BALF. CONCLUSIONS: We conclude that KL-6 and SP-D levels in BALF were increased in pulmonary sarcoidosis. Since these markers are specifically derived from epithelial cells, it is considered that KL-6 and SP-D levels are reflecting damage or release of these markers from epithelial cells due to the inflammatory response.

Adult↗

PubMed2001

Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis.

The caspase cascade is an executioner of apoptosis, mediated by Fas. Fas-associating protein with death domain (FADD) interacts with Fas and initiates apoptosis through activating caspase-8. It has previously been demonstrated that the Fas-Fas ligand pathway may be involved in the pathophysiology of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate Fas-signalling molecules in epithelial cells in IPF. The immunohistochemistry for FADD and caspase-1 and -3 and terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick endlabelling (TUNEL) methods were performed in lung tissues from 10 patients with IPF obtained by thoracoscopic biopsy and in seven normal lung parenchyma specimens. The induction of caspases expression and activation by Fas-ligation on lung epithelial cell line A549 was also investigated. The immunoreactivity grade for FADD and caspase-1 and -3, and positive signals for TUNEL were significantly increased in epithelial cells of IPF compared with controls. Fas-ligation induced upregulation of caspase-1 and -3 expression in the nucleus and cytoplasm in A549 cells. Procaspase-1, -3, and -8 were activated in apoptotic cells, but not in viable cells. Although direct measurement of the caspase activity in lung epithelial cells of idiopathic pulmonary fibrosis could not be made, these results suggest that the Fas-signalling pathway is upregulated in lung epithelial cells of idiopathic pulmonary fibrosis.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Expression of apoptosis-regulatory genes in epithelial cells in pulmonary fibrosis in mice.

Up-regulation of Fas and Fas ligand and excessive apoptosis of bronchiolar and alveolar epithelial cells were identified in bleomycin-induced pulmonary fibrosis in mice. This study hypothesized that apoptosis-regulatory genes other than Fas-Fas ligand, such as p53, p21 (Waf1/Cip1), bcl-2, bcl-x, and bax, may also participate in epithelial cell apoptosis in this model. The expression of these genes was assessed by reverse transcription polymerase chain reaction (RT-PCR), RT in situ PCR, or immunohistochemistry. The expression of p53 and p21 mRNA was concurrently up-regulated in the alveolar epithelial cells at 1 h to 7 days after intratracheal instillation of bleomycin. The expression of bcl-2 mRNA was weakly up-regulated at 1 h to 14 days, while the expression level of bcl-2 protein was not changed. The expression of bcl-x(L) and bax mRNA was strongly up-regulated at 1 h to 7 days. The expression of bcl-x protein was up-regulated in lymphocytes and macrophages, whereas bax protein was up-regulated in both epithelial and inflammatory cells. It is concluded that epithelial cell apoptosis in this model may also be induced by the up-regulation of p53 and bax and by the imbalance between apoptosis-inducible and -inhibitory genes, in addition to the up-regulation of the Fas-Fas ligand pathway.

Animals↗

PubMed2000

Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor.

LPS (lipopolysaccharide) is one of the major factors that induce acute lung injury. Recently, it was reported that LPS induced disseminated endothelial apoptosis, preceding nonendothelial tissue damage. Caspases play important roles in apoptosis, including tumor necrosis factor-alpha-induced apoptosis, in several systems. We therefore investigated whether the injection of a caspase inhibitor prevents LPS-induced apoptosis and acute lung injury in mice. LPS (30 mg/kg) was administered intravenously to Institute for Cancer Research mice. Electron microscopic findings demonstrated characteristic features of apoptosis in endothelial cells and alveolar epithelial cells. The caspase-3 activity and the number of terminal dUTP nick-end labeling-positive cells in lung tissues were significantly increased after LPS administration. Benzyloxycarbonil-Val-Ala-Asp fluoromethylketone (Z-VAD.fmk), which is a broad-spectrum caspase inhibitor, was injected before and after the administration of LPS. The injection of Z-VAD.fmk suppressed the caspase-3 activity in lung tissues, and significantly decreased the number of terminal dUTP nick-end labeling-positive cells. Furthermore, the survival rate of mice was prolonged significantly by the injection of Z-VAD.fmk. These results indicate that apoptosis may play an important role in acute lung injury, and thus that inhibition of caspase activity may constitute a new therapeutic approach for treatment of this disease.

Acute Disease↗

PubMed2000

Analysis of Fas and Fas ligand expression and function in lung cancer cell lines.

The aim of this study was to investigate the expression of Fas and Fas ligand (FasL) and to determine the significance of these molecules in lung cancer cell lines. Immunoblotting, RT-PCR and flow cytometric analyses were carried out to measure the expression of Fas and FasL and to examine their interactions and effects on cell growth and apoptosis. Fas and FasL were co-expressed in most of the cell lines but to varying degrees. Apoptosis induced by the agonistic anti-Fas antibody was significantly correlated with Fas expression (P=0.0075), whereas cisplatin-induced apoptosis was not. Upregulation of Fas and FasL expression by the administration of cisplatin was found in 7 of 11 (64%) and 9 of 11 (82%) cell lines, respectively. However, cisplatin-induced apoptosis was not suppressed by antagonistic anti-FasL antibody. Thus, our data indicated that Fas and FasL were co-expressed in lung cancer cell lines, and that Fas ligation induced by agonistic anti-Fas antibody is functional and induced apoptosis that was dependent on the levels of Fas expression. In contrast, Fas-FasL interactions appeared to be non-functional. Furthermore, our results suggest that cisplatin-induced apoptosis in lung cancer cells was independent of the Fas-FasL interaction.

Antineoplastic Agents↗

PubMed2000

Expression of FasL and Fas protein and their soluble form in patients with hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is characterized by a lymphocytic alveolitis and loosely formed granulomas in lung biopsy specimens. HP improves or disappears altogether after cessation of antigen exposure. The Fas-Fas ligand (FasL) system is one of the representative systems of apoptosis-signaling receptor molecules, and is involved in various inflammatory diseases. We hypothesized that the Fas-FasL system may be associated with this disorder. METHODS: We examined the expression of FasL and Fas proteins in lung tissues from patients with HP using immunohistochemistry. We also measured the soluble form of FasL (sFasL) and sFas levels in serum and bronchoalveolar lavage fluid (BALF) from patients with HP using enzyme-linked immunosorbent assay (ELISA). Furthermore, we also measured the cytotoxic activity of BALF sFasL in vitro. RESULTS: FasL was detected in infiltrating mononuclear cells, and Fas was detected in infiltrating mononuclear cells, alveolar macrophages, and epithelioid cells in HP, whereas FasL was not detected and Fas was detected in few alveolar macrophages in controls. The levels of sFasL and sFas in BALF, but not in serum, were significantly increased in HP compared with controls. BALF of HP that included high levels of sFasL had no cytotoxic activity for bronchiolar epithelial cells in vitro. CONCLUSIONS: In HP, there is an upregulation of FasL and Fas in lung tissues. Since there is no incidence of apoptosis and no cytotoxic activity for lung epithelial cells in BALF from patients with HP, the increased levels of BALF sFasL and sFas may reflect the activation and sequestration of inflammatory cells rather than apoptosis.

Alveolitis, Extrinsic Allergic↗

PubMed2000

Soluble form of fas and fas ligand in BAL fluid from patients with pulmonary fibrosis and bronchiolitis obliterans organizing pneumonia.

STUDY OBJECTIVES: The Fas-Fas ligand (FasL) pathway is a representative system of apoptosis-signaling receptor molecules. We previously described that this pathway may play an important role in the pathogenesis of fibrosing lung diseases. In this study, we hypothesized that soluble form of Fas (sFas) and FasL (sFasL) may also be associated with this disorder. MEASUREMENTS AND RESULTS: We measured sFas and sFasL levels in BAL fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), interstitial pneumonia associated with collagen vascular diseases (CVD-IP), and bronchiolitis obliterans organizing pneumonia (BOOP), using enzyme-linked immunosorbent assay. BALF from all patients was obtained before prednisolone therapy. sFasL levels were relatively increased in IPF patients (p = 0.084), and significantly increased in CVD-IP patients (p < 0.05) and BOOP patients (p < 0.05), compared with control subjects. BALF sFasL levels were elevated in the IPF or CVD-IP subgroups with an indication for prednisolone therapy, compared with those without an indication for therapy. The BALF sFasL level in IPF patients was correlated with the number of total cells and lymphocytes. The BALF sFasL level in BOOP patients was relatively or significantly correlated with the number of total cells or lymphocytes, respectively. The BALF sFas level was significantly increased in BOOP patients, but not in IPF or CVD-IP patients. CONCLUSIONS: We conclude that BALF sFasL levels may be associated with the accumulation of inflammatory cells and reflect the degree of lymphocyte alveolitis in IPF. The elevation of sFasL may be associated with the deterioration of IPF and CVD-IP. The elevation of the BALF sFas level may abrogate the cytotoxicity of FasL in BOOP patients, which may be associated with better prognosis of BOOP, compared with IPF or CVD-IP.

Aged↗

PubMed1999

Expression of B7-1, B7-2, and interleukin-12 in anti-Fas antibody-induced pulmonary fibrosis in mice.

BACKGROUND: We have previously reported that the inhalation of anti-Fas antibody induced pulmonary fibrosis in mice. To induce an effective immune response, antigen-presenting cells have to not only present antigenic peptide with MHC molecules to T lymphocytes, but also express B7 costimulating molecules. The purpose of this study is to investigate whether B7 family costimulating molecules and interleukin-12 (IL-12), which primarily promote cellular immunity, are associated with anti-Fas antibody-induced pulmonary fibrosis. METHODS: We examined the expression of B7-1, B7-2, and IL-12 using the revese transcription-polymerase chain reaction (RT-PCR), RT-in situ PCR, and immunohistochemistry. RESULTS: We observed the upregulation of B7-1, B7-2, and IL-12 p40 mRNA after anti-Fas antibody inhalation. B7-2 and IL-12 p40 mRNA appeared to be expressed in mononuclear cells, while B7-1 mRNA and protein were expressed in bronchiolar epithelial cells as well as macrophages. CONCLUSION: These findings indicate that the T-cell-mediated immune response in this model involved the upregulation of B7-1, B7-2, and IL-12, and that the aberrant expression of B7-1 in bronchiolar epithelial cells may induce autoreactive T cell proliferation against themselves.

Administration, Inhalation↗

PubMed1999

Immunohistochemical localization of B7 costimulating molecules and major histocompatibility complex class II antigen in pulmonary sarcoidosis.

BACKGROUND: Alveolar macrophages (AM) of sarcoidosis have an enhanced capacity to mediate antigen-induced T lymphocyte proliferation. To induce an effective immune response, antigen-presenting cells have to not only present antigenic peptide with MHC molecules to T lymphocytes, but also express B7 costimulating molecules. OBJECTIVE: The purpose of this study was to investigate the expression of B7 and MHC molecules in lung tissues from patients with sarcoidosis. METHODS: We performed immunohistochemistry for B7-1, B7-2 and MHC class II antigens using transbronchial lung biopsy specimens obtained from patients with sarcoidosis and normal lung parenchyma obtained by lobectomy for solitary pulmonary nodule as controls. RESULTS: B7-1, B7-2 and MHC class II antigen were expressed in epithelioid cells in granulomas in 14 (93.3%), 2 (13.3%) and 9 (60.0%) of 15 patients with sarcoidosis, respectively. These were also expressed in AM in 14 (93. 3%), 5 (33.3%) and 12 (80.0%) of 15 patients with sarcoidosis, respectively. The positivity of B7-1 was significantly higher than that of B7-2 in both epithelioid cells and AM in sarcoidosis (p < 0. 01). Positive signals for B7-1, B7-2 and MHC class II antigen were also found in AM in 9 (90%), 8 (80%) and 8 (80%) of 15 of controls, respectively. However, the intensity of positive signals for B7-1, but not B7-2 or MHC class II antigen in AM was significantly increased in sarcoidosis compared to controls (p < 0.05). CONCLUSIONS: These results suggested that epithelioid cells in granulomas and AM from patients with sarcoidosis had the capability to act as accessory cells and that the accessory function of these cells was shifted to B7-1 rather than B7-2 in sarcoidosis.

B7-1 Antigen↗

PubMed1999

Induction of interleukin-8 secretion and apoptosis in bronchiolar epithelial cells by Fas ligation.

Epithelial cell injury is the common manifestation of lung injury. Contributing to such injury of epithelial cells is apoptosis. Although apoptosis is part of the normal process of epithelial renewal, in excess it is pathologic. We previously demonstrated the excessive apoptosis of lung epithelial cells and the upregulation of Fas and Fas ligand (FasL) in fibrosing lung diseases. We also showed that inhalation of anti-Fas antibody induced lung injury and fibrosis in mice. Interleukin (IL)-8 is one of the most important cytokines in the pathophysiology of acute lung injury and pulmonary fibrosis. In this study we investigated whether Fas ligation induces IL-8 secretion in addition to apoptosis in bronchiolar epithelial cells in vitro. Bronchiolar epithelial cells underwent apoptosis and also secreted IL-8 in response to tumor necrosis factor (TNF)-alpha or Fas ligation. New gene expression and protein synthesis were not necessary for Fas ligation- and TNF-alpha- mediated apoptosis, but were necessary for IL-8 secretion. We further found that Fas ligation induced activation of nuclear factor-kappa B. We conclude that the Fas/FasL pathway not only mediates apoptosis but also plays a proinflammatory role, and that stimulation of the Fas/FasL pathway in bronchiolar epithelial cells leads to IL-8 production, which may amplify the inflammatory cascade in lung injury and pulmonary fibrosis.

Antibodies, Monoclonal↗

PubMed1999

Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis.

The Fas ligand is predominantly expressed in activated T lymphocytes and is one of the major effector molecules of cytotoxic T lymphocytes and natural killer cells. Previously, we found excessive apoptosis of epithelial cells and infiltrating lymphocytes expressing Fas ligand mRNA in the lung tissue of bleomycin-induced pulmonary fibrosis in mice. Here we demonstrated that the administration of a soluble form of Fas antigen or anti-Fas ligand antibody prevented the development of this model and that lpr and gld mice were resistant against the induction of pneumopathy. These results suggest that the Fas-Fas ligand pathway plays an essential role in the development of pulmonary fibrosis and that preventing this pathway could have therapeutic value in lung injury and fibrosis.

Animals↗