Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The angiotensin-converting enzyme inhibitor captopril has been shown to inhibit fibrogenesis in the lung, but the mechanisms underlying this action are unclear. Apoptosis of lung epithelial cells is believed to be involved in the pathogenesis of pulmonary fibrosis. For these reasons, we studied the effect of captopril on Fas-induced apoptosis in a human lung epithelial cell line. Monoclonal antibodies that activate the Fas receptor induced epithelial cell apoptosis as detected by chromatin condensation, nuclear fragmentation, DNA fragmentation, and increased activities of caspase-1 and -3. Apoptosis was not induced by isotype-matched nonimmune mouse immunoglobulins or nonactivating anti-Fas monoclonal antibodies. When applied simultaneously with anti-Fas antibodies, 50 ng/ml of captopril completely abrogated apoptotic indexes based on morphology, DNA fragmentation, and inducible caspase-1 activity and significantly decreased the inducible activity of caspase-3. Inhibition of apoptosis by captopril was concentration dependent, with an IC50 of 70 pg/ml. These data suggest that the inhibitory actions of captopril on pulmonary fibrosis may be related to prevention of lung epithelial cell apoptosis.
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PMID:Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. 981 21

Glyoxal is a highly reactive glycating agent involved in the formation of advanced glycation end products (AGEs) and known to induce apoptosis. AGE-mediated apoptosis may be an important mechanism of alveolar epithelial remodelling in pulmonary fibrosis. In this study, we investigated the cytotoxic effect of glyoxal on the fetal human epithelial lung cell line L132 under serum-free conditions. This type of culture, which forces the cells to grow as spheroids, also excludes effects of preformed AGEs by the reaction of glyoxal with fetal calf serum proteins. Our results showed that in cells treated with 200 microM glyoxal, the intercellular contacts in spheroids were disrupted, i.e. cells became totally dissociated. Immunocytochemical analysis revealed a dose-dependent accumulation of the AGE product epsilonN-(carboxymethyl)lysine (CML) in cells detached from cell clusters. The loss of cell attachment was associated with decreased expression of beta1-integrins and CD44 as revealed by laser scanning cytometry (LSC). Increasing concentrations of glyoxal induced an increase in the number of apoptotic cells which were identified by the immunoreactivity for active caspase-3. Remaining cell clusters showed resistance to both CML formation and apoptosis. The present findings demonstrate that cells treated with glyoxal undergo possibly anoikis, a specific mode of apoptosis caused by loss of cell adhesion.
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PMID:Resistance of L132 lung cell clusters to glyoxal-induced apoptosis. 1113 Oct 93

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.
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PMID:Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor. 1115 11

Transforming growth factor-beta 1 (TGF-beta 1) has important roles in lung fibrosis and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary fibrosis. In this study, we show that TGF-beta1 induces apoptosis of primary cultured bronchiolar epithelial cells via caspase-3 activation and down-regulation of cyclin-dependent kinase inhibitor p21. Concentrations of TGF-beta 1 that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas Ab or rFas ligand-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble Fas ligand in the bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-beta Ab. Otherwise, BALF from patients with hypersensitivity pneumonitis (HP) could not induce apoptosis on bronchiolar epithelial cells, despite its comparable amounts of soluble Fas ligand. The concentrations of TGF-beta 1 in BALF from patients with IPF were significantly higher compared with those in BALF from patients with HP or controls. Furthermore, coincubation with the low concentration of TGF-beta 1 and HP BALF created proapoptotic effects comparable with the IPF BALF. In vivo, the administration of TGF-beta 1 could enhance Fas-mediated epithelial cell apoptosis and lung injury via caspase-3 activation in mice. Our results demonstrate a novel role of TGF-beta 1 in the pathophysiology of pulmonary fibrosis as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
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PMID:TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. 1205 67

Acute lung injury (ALI) is characterized by an early inflammatory response followed by a late fibroproliferative phase, and by an increase in the bronchoalveolar lavage fluid (BALF) concentrations of bioactive soluble FasL (sFasL). Activation of Fas (CD95) has been associated with the development of lung fibrosis in mice. The goal of this study was to determine the mechanisms that link Fas activation with the development of fibrosis in the lungs. We treated mice with three daily intratracheal instillations of a Fas-activating monoclonal antibody (Jo2) or a control IgG, and studied the animals at sequential times. Mice treated with Jo2 had increased caspase-3 activation in alveolar wall cells on Days 2, 4, and 7; an inflammatory response peaking on Day 7, and increased total lung collagen on Day 21. Gene expression profiling performed on Days 2, 4, and 7 showed sequential activation of co-regulated profibrotic genes, including marked up-regulation of matrix metalloproteinase 12 (MMP-12). Targeted deletion of MMP-12 protected mice from Fas-induced pulmonary fibrosis, even though the inflammatory responses in the lungs were similar to those of wild-type mice. Compared with wild-type mice, the mmp12(-/-) mice showed decreased expression of the profibrotic genes egr1 and cyr61. We conclude that Fas activation in the lungs induces a complex response that includes apoptosis, inflammation, and eventually fibrosis, and that MMP-12 is essential for the fibrotic phenotype. We speculate that MMP-12 activity is required for activation of the profibrotic genes egr1 and cyr61.
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PMID:Essential role of MMP-12 in Fas-induced lung fibrosis. 1819 46

Myofibroblasts play an essential role in the abnormal deposition of extracellular matrix in pulmonary fibrosis. The presence or prolonged survival of these cells may be a key factor in the pathogenesis of progressive pulmonary fibrosis. Found in inflammatory zone (FIZZ)1 can induce myofibroblast differentiation and has an antiapoptotic effect on embryonic lung explant cultures. In this study, we investigated whether FIZZ1 also has an antiapoptotic effect on mouse lung fibroblasts (MLFs). Cells were treated with FIZZ1 for 24 h and then apoptosis was induced by TNFalpha in the presence of cycloheximide (CHX). FIZZ1 exhibited an antiapoptotic effect in MLFs, as assessed by flow cytometric analysis and TUNEL staining. Moreover, the cell number was higher in the FIZZ1-treated group relative to the non-treated control group after treatment with TNFalpha and CHX. FIZZ1 treatment also inhibited the apoptotic agent-induced activities of caspase-3 and caspase-8. Examination of potential signalling pathways revealed that FIZZ1 induced rapid phosphorylation of ERK-1/2, while PD98059, a MEK/ERK inhibitor, markedly induced activation of caspase-3. This anti-apoptotic effect of FIZZ1 was associated with induction of myofibroblast differentiation in response to FIZZ1 stimulation. Taken together, these findings suggest that FIZZ1 is involved in pulmonary fibrosis through both induction of myofibroblast differentiation and increased or prolonged survival of myofibroblasts. This effect of FIZZ1 was mediated by inhibition of caspase-3 and -8, with involvement of the ERK pathway.
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PMID:Antiapoptotic effect of found in inflammatory zone (FIZZ)1 on mouse lung fibroblasts. 1749 27

Apoptosis of alveolar epithelial cells (AECs) is believed to be critical for the development of bleomycin (BLEO)-induced pulmonary fibrosis. Previous studies showed that apoptosis of alveolar epithelial cells in response to BLEO could be abrogated by antisense oligonucleotides against angiotensinogen (AGT) mRNA and requires angiotensin II (ANG II) synthesis de novo [17]. In this study we hypothesized that blockade of local pulmonary ANG II synthesis by intratracheal (I.T.) administration of antisense oligonucleotides against AGT mRNA might attenuate BLEO-induced apoptosis of AECs and prevent pulmonary fibrosis. In a BLEO-induced rat model of lung fibrosis, endogenous lung AGT was upregulated in vivo as early as 3 hours after BLEO instillation, as detected by RT-PCR, in situ hybridization and immunohistochemistry. AGT mRNA and angiotensin peptides were localized in type II alveolar epithelial cells and also colocalized with alpha-smooth muscle actin (alpha-SMA), a marker of myofibroblasts. Tagged antisense administered I.T. was specifically accumulated by the lung relative to liver and kidney, and localized primarily in the epithelium of airways and cells within alveolar walls. The intratracheal AGT antisense reduced BLEO-induced pulmonary fibrosis measured by lung hydroxyproline assay, decreased lung AGT and active caspase-3 proteins, and reduced the number of apoptotic epithelial cells but had no effect on the serum ANG II concentration. These data are consistent with the hypothesis that lung-derived AGT and local pulmonary ANG II are required for BLEO-induced pulmonary fibrosis, and suggest the possibility of antisense-based manipulation of the local angiotensin system as a potential treatment of fibrotic lung diseases.
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PMID:Attenuation of bleomycin-induced pulmonary fibrosis by intratracheal administration of antisense oligonucleotides against angiotensinogen mRNA. 1750 34

The objective of the study was to determine the presence or levels of antibodies (Abs) against caspase-3 and their clinical relevance in systemic sclerosis (SSc). Anti-caspase-3 Ab was examined by enzyme-linked immunosorbent assay and immunoblotting. IgG anti-caspase-3 Ab levels in SSc patients were higher than in normal controls. SSc patients positive for IgG anti-caspase-3 Ab had significantly longer disease duration, more frequent presence of decreased %VC and %DLco, and elevated levels of serum immunoglobulin and erythrocyte sedimentation rates. IgG anti-caspase-3 Ab levels correlated positively with serum IgG levels, renal vascular resistance, and serum levels of 8-isoprostane. Immunoblotting analysis confirmed the presence of anti-caspase-3 Ab in sera from SSc patients. Caspase-3 enzymatic activity was inhibited by IgG isolated from SSc sera containing IgG anti-caspase-3 Ab. These results suggest that autoantibody against caspase-3 is generated in SSc and that this Ab is related to the severity of pulmonary fibrosis, vascular damage, and inflammation.
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PMID:Autoantibody against caspase-3, an executioner of apoptosis, in patients with systemic sclerosis. 1963 21

Alveolar epithelial cell injury and apoptosis is consistent findings in human idiopathic pulmonary fibrosis (IPF). Epithelial cell apoptosis is known to be induced by leukocyte elastase in vitro. The authors hypothesized that synthetic neutrophil elastase inhibitor, sivelestat (ONO-5046), can inhibit the bleomycin-induced pulmonary fibrosis in rats by blocking the apoptotic pathways in epithelial cells. Adult rats were injected with intratracheal bleomycin. Sivelestat was given for 13 days intraperitoneally after bleomycin treatments. Similar experiments were carried out in which A549 cells, a human alveolar type II epithelial cell line, were treated with bleomycin or neutrophil elastase. In rats, sivelestat decreased neutrophil counts and the cytokine-induced neutrophil chemoattractant (CINC)-1 in the bronchoalveolar lavage (BAL) fluid of bleomycin-treated rats. Sivelestat also decreased the bleomycin-induced lung inflammatory cell apoptosis by decreasing caspase-3 and -9 activities. In A549 cells, sivelestat decreased the elastase-induced epithelial cell apoptosis but not the bleomycin-induced epithelial cell apoptosis. Similarly, sivelestat inhibited the elastase-induced cell death but not the bleomycin-induced cell death in MTT assays. Sivelestat also inhibited the elastase-induced caspase-3 and -9 activities and cytochrome c release from the mitochondria but did not inhibit the bleomycin-induced caspase activities in A549 cells. In conclusion, bleomycin caused the lung inflammatory cell apoptosis through the caspase-9 and -3 pathways in rats. Sivelestat inhibited pulmonary fibrosis by blocking these mitochondria-mediated apoptotic pathways in bleomycin-treated rats and in elastase-treated A549 cells. These findings suggest that sivelestat can suppress the bleomycin-induced pulmonary fibrosis by blocking neutrophil chemotaxis and by inhibiting the neutrophil elastase-induced lung cell apoptosis in rats.
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PMID:Effects of elastase inhibitor on the epithelial cell apoptosis in bleomycin-induced pulmonary fibrosis. 1999 76

Bleomycin, a chemotherapeutic agent, can cause pulmonary fibrosis in humans and is commonly used to induce experimental pulmonary fibrosis in rodents. In cell culture, bleomycin causes single- and double-stranded DNA breaks and produces reactive oxidative species, both of which require iron (Fe(2+)) and O(2). The mechanism of bleomycin-induced apoptosis is controversial due to its complexity. We investigated bleomycin apoptotic signaling events in primary pulmonary endothelial cells. Time course experiments revealed that bleomycin induced apoptosis within 4 h. Caspase-8, the initiator caspase for the extrinsic pathway, was activated within 2 h and preceded activation of the effector caspases-3 and -6 (4 h). Caspase-9, the initiator of the intrinsic pathway and release of cytochrome c from the mitochondria were not detected at these time points. Bleomycin induced the expression of Bcl-2 and Bcl-x(L), Bcl-2 family member proteins that protect cells from the mitochondria-dependent intrinsic apoptosis. Real-time quantitative RT-PCR results demonstrated that, at 4-8 h, bleomycin induced expression of TNF and TNF receptor family genes known to induce the extrinsic apoptotic pathway. Silencing of the death receptor adaptor protein Fas-associated death domain by short interfering RNA significantly reduced bleomycin-induced apoptosis. Apoptosis was also abrogated by caspase-8 inhibition, but only slightly reduced by caspase-3 inhibition. Together, these data suggest that bleomycin initiates apoptosis via the extrinsic pathway.
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PMID:Bleomycin induces the extrinsic apoptotic pathway in pulmonary endothelial cells. 2015 24


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