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)

Reactive oxygen species (ROS) play an important role in the pathogenesis of many human diseases, including the acute respiratory distress syndrome, Parkinson's disease, pulmonary fibrosis, and Alzheimer's disease. In mammalian cells, several genes known to be induced during the immediate early response to growth factors, including the protooncogenes c-fos and c-myc, have also been shown to be induced by ROS. We show that members of the STAT family of transcription factors, including STAT1 and STAT3, are activated in fibroblasts and A-431 carcinoma cells in response to H2O2. This activation occurs within 5 min, can be inhibited by antioxidants, and does not require protein synthesis. STAT activation in these cell lines is oxidant specific and does not occur in response to superoxide- or nitric oxide-generating stimuli. Buthionine sulfoximine, which depletes intracellular glutathione, also activates the STAT pathway. Moreover, H2O2 stimulates the activity of the known STAT kinases JAK2 and TYK2. Activation of STATs by platelet-derived growth factor (PDGF) is significantly inhibited by N-acetyl-L-cysteine and diphenylene iodonium, indicating that ROS production contributes to STAT activation in response to PDGF. These findings indicate that the JAK-STAT pathway responds to intracellular ROS and that PDGF uses ROS as a second messenger to regulate STAT activation.
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PMID:Activation of the JAK-STAT pathway by reactive oxygen species. 984 26

Transforming growth factor beta (TGFbeta) may play an important role in diseases characterized by pulmonary fibrosis. We have previously demonstrated that thiols inhibit the pro-oxidant effects of TGFbeta1 in bovine pulmonary artery endothelial cells (BPAEC). To help define the mechanism of this observation we have examined the effect of reduced (GSH) and oxidized (GSSG) glutathione, N-acetyl cysteine (NAC) and cysteine (CYS) on the biological activity of a) TGFbeta released by bovine pulmonary artery endothelial cells (BPAEC) into culture medium, and b) commercially available porcine platelet TGFbeta1. The biological activity of TGFbeta (following activation) released into the medium from cultured BPAEC was significantly reduced when the cells were cultured in the presence of 10 mM GSH or 10 mM NAC for 24 h (10 mM GSH: 85.7 +/- 50 pg/ml/10(6) cells and 10 mM NAC: 127.3 +/- 35 pg/ml/10(6) cells, compared with control: 541 +/- 8.9 pg/ml/10(6) cells; p < 0.05). Thiols (10 mM GSH, 10 mM NAC and 5 mM cysteine), added directly to cell-free conditioned medium or to a commercially available preparation of porcine platelet TGFbeta1 for 6-24 h had a similar inhibitory effect on the biological activity of TGFbeta and altered the structure of porcine platelet TGFbeta1 as determined by mass spectroscopy. These thiols failed to reduce the expression of TGFbeta mRNA in BPAEC as measured by a competitive polymerase chain reaction assay. Incubating endothelial cells or cell-free conditioned medium with GSSG did not alter the biological activity of TGFbeta. Lower doses of thiols (0.1-1 mM), that we have shown inhibit the antiproliferative and pro-oxidant effects of exogenous TGFbeta1 on BPAEC, had no direct effect on TGFbeta bioactivity. In summary, thiols are capable of reducing the effects of TGFbeta in biological systems through a direct effect on the TGFbeta molecule. However, this action appears to be dose-dependent, and at low doses (0.1-1 mM) thiols may also inhibit the actions of exogenous TGFbeta1 in cell culture through a mechanism involving the cellular redox status.
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PMID:Reduction of endothelial cell related TGFbeta activity by thiols. 1036 74

SPARC (secreted protein, acidic and rich in cysteine) is a component of the matrix that appears to regulate tissue remodeling. There is evidence that it accumulates in the lung in the setting of pulmonary injury and fibrosis, but direct evidence of its involvement is only now emerging. We therefore investigated the development of pulmonary fibrosis induced by bleomycin administered either intratracheally or intraperitoneally in mice deficient in SPARC. Bleomycin (0.15 U/mouse) given intratracheally induced significantly more pulmonary fibrosis in mice deficient in SPARC compared with that in wild-type control mice, with the mutant mice demonstrating greater neutrophil accumulation in the lung. However, in wild-type and SPARC-deficient mice given intraperitoneal bleomycin (0.8 U/injection x 5 injections over 14 days), the pattern and severity of pulmonary fibrosis, as well as the levels of leukocyte recruitment, were similar in both strains of mice. These findings suggest that the involvement of SPARC in pulmonary injury is likely to be complex, dependent on several factors including the type, duration, and intensity of the insult. Furthermore, increased neutrophil accumulation in the peritoneal cavity was also observed in SPARC-null mice after acute chemical peritonitis. Together, these data suggest a possible role for SPARC in the recruitment of neutrophils to sites of acute inflammation.
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PMID:Bleomycin-induced pulmonary injury in mice deficient in SPARC. 1100 Jan 35

To investigate repair mechanisms in bleomycin-induced pulmonary fibrosis, we used mice deficient in gamma-glutamyl transpeptidase (GGT-/-), a key enzyme in glutathione (GSH) and cysteine metabolism. Seventy-two hours after bleomycin (0.03 U/g), GGT-/- mice displayed a different inflammatory response to wild-type mice as judged by a near absence of neutrophils in lung tissue and bronchoalveolar lavage and a less pronounced rise in matrix metalloproteinase-9. Inflammation in GGT-/- mice consisted mainly of lymphocytes and macrophages. At 1 month, lungs from bleomycin-treated GGT-/- mice exhibited minimal areas of fibrosis compared with wild-type mice(light microscopy fibrosis index: 510 +/- 756 versus 1975 +/- 817, p < 0.01). Lung collagen content revealed a significant increase in bleomycin-treated wild-type (15.1 +/- 3.8 versus 8.5 +/- 0.7 microg hydroxy(OH)-proline/mg dry weight, p < 0.01) but not in GGT-/- (10.4 +/- 1.7 versus 8.8 +/- 0.8). Control lungs from GGT-/- showed a significant reduction of cysteine (0.03 +/- 0.005 versus 0.055 +/- 0.001, p < 0.02) and GSH levels (1.24 +/- 0.055 versus 1.79 +/- 0.065, p < 0.002). These values decreased after 72 hours of bleomycin in both GGT-/- and wild-type but reached their respective control values after 1 month. Supplementation with N-acetyl cysteine partially ameliorated the effects of GGT deficiency. These findings suggest that increased neutrophils and matrix metalloproteinase-9 during the early inflammatory response and adequate thiol reserves are key elements in the fibrotic response after bleomycin-induced pulmonary injury.
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PMID:Bleomycin-induced pulmonary fibrosis is attenuated in gamma-glutamyl transpeptidase-deficient mice. 1246 40

Fibroproliferative response of rat heart and lung fibroblasts to the lanthanide cerium was examined, as the element has been implicated in the causation of cardiac and pulmonary fibrosis. Fibroblasts from both of the organs were morphologically identical, and the response to fetal bovine serum, a nonspecific mitogen, was also comparable. The oxygen radical generator (hypoxanthine + xanthine oxidase [Hyp. + XO]) induced a proliferative response that was neutralized in both cardiac and lung fibroblasts by free-radical scavengers. Superoxide dismutase was more effective than catalase in reducing the mitogenic effect of Hyp. + XO. The free-radical scavenger N-acetyl-L-cysteine neutralized the free-radical-mediated changes in pulmonary fibroblasts but had a negative effect in cardiac fibroblasts, indicating a tissue-dependent variation. Reactive oxygen species are known to act as biological mediators of tissue fibrosis induced by metallic compounds. Exposure to low levels of cerium (0.5 microM) stimulated a mitogenic response in cardiac fibroblasts, but the pulmonary fibroblasts were not sensitized by the element. Tissue-dependent variation in proliferative response to cerium shows a positive association with intracellular generation of reactive oxygen species. Fibrotic changes in cerium pneumoconiosis may either be replacement fibrosis following tissue damage or mediated by nonfibroblastic cells. The study confirms that cardiac and pulmonary fibroblasts are dissimilar cellular subtypes.
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PMID:Variation in mitogenic response of cardiac and pulmonary fibroblasts to cerium. 1297 91

Endogenous inhibitors tightly control the activity of proteinases in the extracellular space. Proteinase/antiproteinase imbalance may be caused by predominance of proteinases, resulting in severe tissue damage or abundance of proteinase inhibitors, leading to a shift in the balance of synthesis and degradation of extracellular matrix proteins and accumulation of these matrix components. Lung fibrosis is characterised by accumulation of fibrous matrix proteins in the alveolar interstitium. The activity of cathepsin D and amounts of cathepsins D and B in bleomycin-injured rat lung tissue and alveolar macrophages were examined. In addition, the activities of cathepsins and cysteine proteinase inhibitors (CPIs) in bronchoalveolar lavage fluid (BALF) were determined. No cathepsin but high CPI activity and large amounts of procathepsin B were detected in the BALF. In the alveolar lumen, the disturbed proteinase/antiproteinase balance for cysteine proteinases was clearly dominated by CPIs. In alveolar macrophages, the main source of increased cathepsin levels, large changes in cathepsin B and D content were observed during the inflammatory phase, corresponding to the occurrence of procathepsin B in BALF. With the end of the phase of tissue remodelling, imbalances in cathepsin and CPI activities were largely eliminated. Immunoblot data, revealing an increase in cathepsin D levels in myofibroblast-like cells compared to fibroblasts and in resting fibroblasts compared to proliferating cells, implicate this proteinase in the differentiation and conversion processes occurring at the beginning of the fibrotic phase of lung injury. The results show that cathepsin amounts and activities are increased transiently in lung tissue during regeneration processes in bleomycin-induced lung injury. Imbalances of cathepsin and cysteine proteinase inhibitors activities are also a phenomenon of the phase of tissue remodelling initiated by lung injury.
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PMID:Cathepsins in bleomycin-induced lung injury in rat. 1451 31

Pirfenidone is a newly developed antifibrotic drug that has been reported to retard the progression of pulmonary fibrosis induced by bleomycin and cyclophosphamide in animal models of lung fibrosis. The present in vitro studies using noncellular and cellular systems evaluated the antioxidant and cytotoxic properties of this drug. The Fenton reaction [Fe(II) + H2O2 --> Fe(III) + *OH + OH-] and the xanthine/xanthine oxidase system were used as sources of hydroxyl (*OH) and superoxide anion (O2*-) radicals, respectively. Electron spin resonance spin trapping was used for free radical detection and measurement. The reaction rate of pirfenidone with *OH was found to be 1.63 x 10(10) M(-1) s(-1), which is comparable to several well-established antioxidants, such as ascorbate, glutathione, cysteine, azide, and lipoic acid. Compared to *OH radicals, the O2*- scavenging was less efficient 42.36 M(-1) s(-1) with pirfenidone. Pirfenidone was also effective in inhibiting zymosan-stimulated chemiluminescence. In a noncellular model of lipid peroxidation, pirfenidone inhibited crystalline silica-induced lipid peroxidation. The inhibition of crystalline silica-induced cytotoxic reactions and lipid peroxidation combined with the efficient antioxidant properties of pirfenidone indicate that this agent may express its antifibrotic effects partly through its ability to scavenge reactive oxygen species.
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PMID:Effects of pirfenidone on the generation of reactive oxygen species in vitro. 1528 Dec 29

This study examined effects of S-allyl cysteine (SAC) on carbon tetrachloride (CCl4)-induced interstitial pulmonary fibrosis in Wistar rats. CCl4 (0.5 ml/kg) was intraperitoneally injected into rats twice a week for 8 weeks, and SAC (50, 100, or 200 mg/kg), N-acetyl cysteine (NAC, 200 or 600 mg/kg), or L-cysteine (CYS, 600 mg/kg) were orally administrated to rats everyday for 8 weeks. SAC significantly reduced the increases of transforming growth factor beta, lipid peroxides, AST, and ALT in plasma, induced by CCl4. Although CCl4 is mainly metabolized by hepatic cytochrome P450, CCl4 induced systemic inflammation and some organ fibrosis. SAC dose-dependently and significantly attenuated CCl4-induced systemic inflammation and fibrosis of lung. SAC also inhibited the decrease of thiol levels, the increase of inducible nitric oxide synthase expression, the infiltration of leukocytes, and the generation of reactive oxygen species in lungs. Although NAC and CYS attenuated CCl4-induced pulmonary inflammation and fibrosis, the order of preventive potency was SAC > NAC > CYS according to their applied doses. These results indicate that SAC is more effective than other cysteine compounds in reducing CCl4-induced lung injury, and might be useful in prevention of interstitial pulmonary fibrosis.
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PMID:S-allyl cysteine attenuated CCl4-induced oxidative stress and pulmonary fibrosis in rats. 1661 85

Expression of transforming growth factor alpha (TGF-alpha) in the respiratory epithelium of transgenic mice caused pulmonary fibrosis, cachexia, pulmonary hypertension, and altered lung function. To identify genes and molecular pathways mediating lung remodeling, mRNA microarray analysis was performed at multiple times after TGF-alpha expression and revealed changes consistent with a role for TGF-alpha in the regulation of extracellular matrix and vasculogenesis. Transcripts for extracellular matrix proteins were augmented along with transcripts for genes previously identified to have roles in pulmonary fibrosis, including tenascin C, osteopontin, and serine (or cysteine) peptidase inhibitor, clade F, member 1. Transcripts regulating vascular processes including endothelin receptor type B, endothelial-specific receptor tyrosine kinase, and caveolin, caveolae protein 1 were decreased. When TGF-alpha expression was no longer induced, lung remodeling partially reversed and lung function and pulmonary hypertension normalized. Transcripts increased during resolution included midkine, matrix metalloproteinase 2, and hemolytic complement. Hierarchical clustering revealed that genes regulated by TGF-alpha were similar to those altered in the lungs of patients with idiopathic pulmonary fibrosis. These studies support a role for epithelial cell-derived TGF-alpha in the regulation of processes that alter the airway and vascular architecture and function.
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PMID:Genomic profile of matrix and vasculature remodeling in TGF-alpha induced pulmonary fibrosis. 1749 52

Induction of apoptosis by silica in alveolar macrophages (AM) may be a critical step in silica-induced lung injury and pulmonary fibrosis. This study investigated the mechanism(s) through which silica induces apoptosis in AM and their production of proinflammatory cytokines. Using N-acetyl-L-cysteine (NAC) for glutathione (GSH) synthesis and removal of reactive oxygen species (ROS), and rhodamine 6G (R6G) to inhibit the mitochondrial-dependent function, this study found that silica-induced apoptosis of rat AM in primary culture is mitochondria dependent and exhibits a mechanism involving ROS generation, increased mitochondrial release of cytochrome c, and the activation of caspase 9, but not caspase 8, activity. Silica-induced apoptosis was accompanied by a lowering of intracellular and mitochondrial GSH (mGSH) and was blocked by pretreatment of cells with NAC or R6G. When cells were exposed to silica and then treated with either NAC or R6G, silica-induced apoptosis was not affected by the blocking agent. In addition, R6G, which inhibited cellular ATP production and mitochondrial ROS generation, had no effect on apoptosis induced by exogenous hydrogen peroxide or superoxide. Pretreatment of cells with NAC or R6G also inhibited silica-induced production of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, but the inhibition of these cytokines with agents known to block their secretion did not protect cells from silica-induced apoptosis. Data indicate that silica-induced apoptosis is mediated through mitochondrial generation of ROS, which may be inhibited by pretreatment of cells with R6G that prevents ROS generation, or with NAC that maintains a high level of mGSH. The secretion of IL-1beta and TNF-alpha by silica-exposed AM was markedly inhibited by NAC and R6G, suggesting that the production of these cytokines is also ROS dependent.
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PMID:Role of mitochondria in silica-induced apoptosis of alveolar macrophages: inhibition of apoptosis by rhodamine 6G and N-acetyl-L-cysteine. 1768 26


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