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)

We have investigated a potential role for tumor necrosis factor (TNF)-alpha and its two receptors (p55 and p75) in lung injury. We used several varieties of mice exposed endotracheally to two fibrogenic agents, silica (0.2 g/kg) and bleomycin (4 U/kg). The lungs were analyzed at 14 and 28 d after exposure to bleomycin or silica, respectively, for TNF and TNF receptor (TNFR) messenger RNA (mRNA), hydroxyproline content, and histopathology. Silica induced increased (over saline-treated animals) expression of TNF mRNA in double TNFR knockout (Ko), C57BL/6, BALB/c, and 129/J mice. In contrast, bleomycin increased expression in all but BALB/c mice, which are resistant to the fibrogenic effects of this drug. mRNA expression of both receptors was constitutively expressed in all of the normal murine strains. Silica upregulated expression of the p75 receptor, but not the p55 receptor, in the C57BL/6, BALB/c, and 129/J mice. In comparison, bleomycin had little effect on either receptor in the bleomycin-resistant BALB/c mice. Hydroxyproline content of the lungs after treatment followed this same pattern, with significant increases caused by silica in the C57BL/6, BALB/c, and 129/J mice, whereas bleomycin caused no apparent increases in the BALB/c mice. Even though silica and bleomycin induced increases in TNF in the TNFR Ko mice, the mice were protected from the fibrogenic effects of these agents. This study supports the concept that TNF is a central mediator of interstitial pulmonary fibrosis.
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PMID:Upregulation of the p75 but not the p55 TNF-alpha receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice. 1010 Oct 16

Silicosis is a serious occupational lung disease associated with irreversible pulmonary fibrosis. The interaction between inhaled crystalline silica and the alveolar macrophage (AM) is thought to be a key event in the development of silicosis and fibrosis. Silica can cause direct injury to AMs and can induce AMs to release various inflammatory mediators. Acute silicosis is also characterized by a marked elevation in surfactant apoprotein A (SP-A); however, the role of SP-A in silicosis is unknown. We investigated whether SP-A directly affects the response of AMs to silica. In this study, the degree of silica toxicity to cultured rat AMs as assessed by a (51)Cr cytotoxicity assay was shown to be dependent on the time of exposure and the concentration and size of the silica particles. Silica directly injured rat AMs as evidenced by a cytotoxic index of 32.9 +/- 2.5, whereas the addition of rat SP-A (5 microg/ml) significantly reduced the cytotoxic index to 16.6 +/- 1.2 (P < 0. 001). This effect was reversed when SP-A was incubated with either polyclonal rabbit anti-rat SP-A antibody or D-mannose. These data indicate that SP-A mitigates the effect of silica on AM viability, and this effect may involve the carbohydrate recognition domain of SP-A. The elevation of SP-A in acute silicosis may serve as a normal host response to prevent lung cell injury after exposure to silica.
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PMID:Surfactant protein A prevents silica-mediated toxicity to rat alveolar macrophages. 1074 48

The dynamic mechanical properties of lung tissue and its contents of collagen and elastic fibers were studied in strips prepared from mice instilled intratracheally with saline (C) or silica [15 (S15) and 30 days (S30) after instillation]. Resistance, elastance, and hysteresivity were studied during oscillations at different frequencies on S15 and S30. Elastance increased from C to silica groups but was similar between S15 and S30. Resistance was augmented from C to S15 and S30 and was greater in S30 than in S15 at higher frequencies. Hysteresivity was higher in S30 than in C and S15. Silica groups presented a greater amount of collagen than did C. Elastic fiber content increased progressively along time. This increment was related to the higher amount of oxytalan fibers at 15 and 30 days, whereas elaunin and fully developed elastic fibers were augmented only at 30 days. Silicosis led not only to pulmonary fibrosis but also to fibroelastosis, thus assigning a major role to the elastic system in the silicotic lung.
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PMID:Lung tissue mechanics and extracellular matrix composition in a murine model of silicosis. 1124 40

Silica has been known to be a factor in acute cell injury and chronic pulmonary fibrosis. In Rat2 fibroblasts, silica induced the activation of nuclear factor-kappa B (NF-kappaB), which plays a crucial role in regulating the expression of many genes involved in the subsequent inflammatory response. In addition, we observed that transforming growth factor-beta activated kinase 1 (TAK1) and NF-kappaB-inducing kinase (NIK) were involved in silica-mediated NF-kappaB activation in Rat2 cells. The dominant negative mutant forms of TAK1 and NIK inhibited the silica-induced NF-kappaB activation in Rat2 cells. Furthermore, we demonstrated that endogenous TAK1 is phosphorylated in silica-stimulated Rat2 cells. These results indicate that TAK1 functions as a critical mediator in the silica-induced signaling pathway.
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PMID:Silica induces nuclear factor-kappaB activation through TAK1 and NIK in Rat2 cell line. 1284 93

Silica is a causative factor of acute cell injury in pulmonary fibrosis. Inducible cyclooxygenase-2 (COX-2) was suggested to play a role in the process of inflammation and fibrosis. We report that silica induces COX-2 expression in WI-38 fibroblasts. Further analysis showed that silica activated the transcription of COX-2 gene primarily via a nuclear factor (NF)-kB binding site in the promoter. NF-kB-inducing kinase (NIK) and TGF-k activated kinase 1 (TAK1), the upstream signaling molecules of NF-kB, are involved in the silica-mediated COX-2 expression. The Electrophoretic Mobility Shift Assay (EMSA) showed that silica induced the direct binding of NF-kB on the putative binding site in COX-2 promoter. These results suggest that silica activates the human COX-2 gene transcription through the induction of NF-kB activity.
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PMID:Silica induces human cyclooxygenase-2 gene expression through the NF-kappaB signaling pathway. 1605 Aug 1

Silica has been known to be a factor inducing acute injury and chronic pulmonary fibrosis. Silica has also been listed as a human carcinogen in 1996 by International Agency for Research on Cancer (IARC). However, the molecular mechanisms involved its pathologic effects are not well understood. In these studies, we found that exposure of human embryonic lung fibroblasts (HELF) to crystalline silica could cause increases in activation of extracellular signal-regulated kinases (ERKs), p38K, and c-Jun NH2-terminal amino kinases (JNKs), and HELF transformation. Interestingly, silica-induced transformation of HELF (S-HELF) led to increases in activated levels of ERKs and p46 of JNKs, and decrease in p38K activation, and no effect on activation of p54 of JNKs, as compared with those in parental HELF. Further studies showed that there are differential effects of ERKs, JNKs and p38K, as well as their downstream transcription factor AP-1, in regulation of expression of cyclin D1 and CDK4 and cell cycle alternations induced by silica. Cyclin D1 and CDK4 were increased in S-HELF as compared with those in HELF. Inhibition of ERKs activation by AG126, JNK by SP600125, and AP-1 by curcumin could reduced the induction of cyclin D1 and CDK4. There is no significant difference for cell cycle distribution between groups. These results demonstrate that ERKs and JNKs, but not p38K is responsible for induction of cyclin D1 and CDK4 in S-HELF, suggesting that overexpression of cyclin D1 and CDK4 caused by silica is mediated by ERK, JNK/AP-1signaling pathway.
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PMID:Overexpression of cyclin D1-CDK4 in silica-induced transformed cells is due to activation of ERKs, JNKs/AP-1 pathway. 1612 82

Inhalation of crystalline silica results in pulmonary fibrosis and silicosis. It has been suggested that mast cells play a role in these conditions. How mast cells would influence pathology is unknown. We thus explored mast cell interactions with silica in vitro and in B6.Cg-kit(W-sh) mast cell-deficient mice. B6.Cg-kit(W-sh) mice did not develop inflammation or significant collagen deposition after instillation of silica, while C57Bl/6 wild-type mice did have these findings. Given this supporting evidence of a role for mast cells in the development of silicosis, we examined the ability of silica to activate mouse bone marrow-derived mast cells (BMMC), including degranulation (beta-hexosaminidase release); production of reactive oxygen species (ROS) and inflammatory mediators; and the effects of silica on Fc epsilon RI-dependent activation. Silica did not induce mast cell degranulation. However, TNF-alpha, IL-13, monocyte chemotactic protein-1, protease activity, and production of ROS were dose-dependently increased after silica exposure, and production was enhanced after Fc epsilon RI stimulation. This mast cell activation was inhibited by anti-inflammatory compounds. As silica mediates some effects in macrophages through scavenger receptors (SRs), we first determined that mast cells express scavenger receptors; then explored the involvement of SR-A and macrophage receptor with colleagenous structure (MARCO). Silica-induced ROS formation, apoptosis, and TNF-alpha production were reduced in BMMC obtained from SR-A, MARCO, and SR-A/MARCO knockout mice. These findings demonstrate that silica directs mast cell production of inflammatory mediators, in part through SRs, providing insight into critical events in the pathogenesis and potential therapeutic targets in silicosis.
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PMID:Silica-directed mast cell activation is enhanced by scavenger receptors. 1690 92

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

Silica is a factor in the induction of acute injury and chronic pulmonary fibrosis. In 1996, silica was also listed as a human carcinogen by the International Agency for Research on Cancer (IARC). However, the molecular mechanisms involved in its pathologic effects are not well understood. We found that exposure of human embryonic lung fibroblasts (HELF) to crystalline silica for 2h decreased cyclin D1 and cyclin-dependent kinase 4 (CDK4) expression levels. Extracellular signal-regulated protein kinase (ERKs), c-Jun NH2-terminal amino kinase (JNKs), and p38 kinase, as well as their downstream transcription factor, AP-1, had different effects on the regulation of expression levels of cyclin D1 and CDK4 alterations induced by silica. Silica activates multiple signal transduction pathways involved in coordinating cellular responses to stress. We established the requirements for ERK and JNK, members of the mitogen-activated protein kinase (MAPK) family, in mediating G1 phase arrest of HELF induced by silica. Silica treatment activated ERK in a dose-dependent manner. AG126 (a chemical inhibitor of the ERK signaling pathway) and the dominant negative mutant of ERK2 (a molecular inhibitor of ERK2) prevented decreases in cyclin D1 and CDK4 expression levels. A chemical inhibitor of JNK, SP600125, prevented the decreased expression of both cyclin D1 and CDK4, whereas SB203580, a chemical inhibitor of p38, did not. Interestingly, curcumin prevented the decrease in DK4 expression, but not in cyclin D1. These results demonstrate that ERKs and JNKs are responsible for the decrease of cyclin D1 and CDK4 expression levels in HELF induced by silica. Activator protein-1 (AP-1) was responsible for the decrease of CDK4 expression level, but not that of cyclin D1. The findings help to explain the mechanisms of diseases induced by silica.
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PMID:Downregulation of cyclin D1-CDK4 protein in human embryonic lung fibroblasts (HELF) induced by silica is mediated through the ERK and JNK pathway. 1870 51

ABSTRACT Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the silica-induced pulmonary fibrosis. The effect of silica on the expression of PAI-1 was investigated in human lung epithelial cells (A549). Silica induced PAI-1 expression in a concentration-(50-200 mug/mL) and time-(4-24 h) dependent manner in A549 cells. Furthermore, the roles of mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathways in silica-induced PAI-1 expression were examined. We found that silica (200 mug/mL) treatment for 4 to 24 h resulted in AP-1 activation in A549 cells. Cells were pretreated with the AP-1 inhibitor curcumin (10, 25, 50 muM), and silica-induced PAI-1 expression was reduced by 20%, 63%, and 65%, respectively. In addition, dominant-negative mutant c-Jun (TAM67) down-regulated silica-induced PAI-1 expression by 59%. P38 kinase inhibitor SB203580 (20 muM) and Erk inhibitor PD98059 (50 muM) suppressed silica-induced PAI-1 expression by 35% and 51%, respectively. Additionally, PD98059 but not SB203580 inhibited the AP-1 DNA binding activity induced by silica. The results suggest that the PAI-1 expression induced by silica may be involved in the activation of MAPKs/AP-1 signaling pathways in human lung epithelial cells.
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PMID:Silica Induces Plasminogen Activator Inhibitor-1 Expression through a MAPKs/AP-1-Dependent Mechanism in Human Lung Epithelial Cells. 2002 Aug 54


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