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)

Upregulation of the platelet-derived growth factor (PDGF) receptor-alpha (PDGFR-alpha) is a mechanism of myofibroblast hyperplasia during pulmonary fibrosis. We previously identified interleukin (IL)-1beta as a major inducer of the PDGFR-alpha in rat pulmonary myofibroblasts in vitro. In this study, we report that staurosporine, a broad-spectrum kinase inhibitor, upregulates PDGFR-alpha gene expression and protein. A variety of other kinase inhibitors did not induce PDGFR-alpha expression. Staurosporine did not act via an IL-1beta autocrine loop because the IL-1 receptor antagonist protein did not block staurosporine-induced PDGFR-alpha expression. Furthermore, staurosporine did not activate a variety of signaling molecules that were activated by IL-1beta, including nuclear factor-kappaB, extracellular signal-regulated kinase, and c-Jun NH2-terminal kinase. However, both staurosporine- and IL-1beta-induced phosphorylation of p38 mitogen-activated protein kinase and upregulation of PDGFR-alpha by these two agents was inhibited by the p38 inhibitor SB-203580. Finally, staurosporine inhibited basal and PDGF-stimulated mitogenesis over the same concentration range that induced PDGFR-alpha expression. Collectively, these data demonstrate that staurosporine is a useful tool for elucidating the signaling mechanisms that regulate PDGFR expression in lung connective tissue cells and possibly for evaluating the role of the PDGFR-alpha as a growth arrest-specific gene.
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PMID:Regulation of PDGFR-alpha in rat pulmonary myofibroblasts by staurosporine. 1115 15

Basic fibroblast growth factor (bFGF) is a potent mitogenic factor for smooth muscle cells, myofibroblasts, and fibroblasts, proliferation of which is a hallmark of idiopathic pulmonary fibrosis (IPF) and lymphangioleiomyomatosis (LAM). Mast cells produce bFGF and have been associated with pulmonary fibrosis. We hypothesize that smooth muscle cell/myofibroblast-like cells will be spatially associated with bFGF-containing mast cells and that bFGF receptors will be expressed on the effector cells in IPF and LAM. We performed quantitative immunohistochemistry for bFGF, mast cell tryptase, smooth muscle actin for smooth muscle cell/myofibroblast-like cells, and fibroblast growth factor receptors (Flg, Bek) and measured collagen and elastic fiber in lung sections from IPF (n = 14), LAM (n = 9), and control lung (n = 10). IPF and LAM lung contained more smooth muscle cell/myofibroblast-like cells than did control lung. bFGF-containing mast cells were abundant both in IPF and LAM and were associated with collagen, elastic fibers, and smooth muscle cell/myofibroblast-like cells in IPF. Flg was expressed on epithelial cells, endothelial cells, smooth muscle cell/myofibroblast-like cells, and macrophages in IPF. In LAM, Flg was expressed on epithelial cells adjacent to smooth muscle cell/myofibroblast-like cell aggregates. Bek was expressed dominantly on smooth muscle cell/myofibroblast-like cells in LAM and on smooth muscle cell/myofibroblast-like cells as well as neutrophils in IPF. These data suggest that mast cell-derived bFGF might exert fibrogenic, proliferative effects on smooth muscle cell/myofibroblast-like cells through its receptors.
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PMID:Basic fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis and lymphangioleiomyomatosis. 1220 79

The development of fibrosis is a common response to a variety of injuries and results in the net accumulation of matrix proteins and impairment of normal organ function. We previously reported that the integrin alpha8beta1 is expressed by alveolar interstitial cells in normal lung and is upregulated during the development of fibrosis. TGFbeta1 is an important mediator of the inflammatory response in pulmonary fibrosis. TGFbeta1 is secreted as a latent protein that is non-covalently associated with latency-associated peptide (LAP) and requires activation to exert its effects. LAP-TGFbeta1 and LAP-TGFbeta3 contain the tripeptide sequence, arginine-glycine-aspartic acid (RGD), a known integrin recognition motif. The integrin alpha8beta1 binds to several ligands such as fibronectin and vitronectin through the RGD sequence. Recent reports demonstrate that the integrins alphavbeta1, alphavbeta6 and alphavbeta8 adhere to LAP-TGFbeta1 through the RGD site. Therefore, we asked whether LAP-TGFbeta1 might be a ligand for alpha8beta1 and whether this may be important in the development of fibrosis. We found that cell lines transfected with alpha8 subunit were able to spread on and adhere to recombinant LAP-TGFbeta1 significantly better than mock transfected cell lines. alpha8-transfected cells were also able to adhere to LAP-TGFbeta3 significantly better than mock transfected cells. Adhesion to LAP-TGFbeta1 was enhanced by activation of alpha8beta1 by Mn(2+), or 8A2, an integrin beta1 activating antibody. Furthermore, cell adhesion was abolished when we used a recombinant LAP-TGFbeta1 protein in which the RGD site was mutated to RGE. alpha8beta1 binding to LAP-TGFbeta1 increased cell proliferation and phosphorylation of FAK and ERK, but did not activate of TGFbeta1. These data strongly suggest that LAP-TGFbeta1 is a ligand of alpha8beta1 and interaction of alpha8beta1 with LAP-TGFbeta1 may influence cell behavior.
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PMID:Integrin alpha8beta1 mediates adhesion to LAP-TGFbeta1. 1241 8

Asbestos fibers up-regulate the extracellular signal-regulated kinase (ERK1/2) pathway in mesothelial and pulmonary epithelial cells in vitro, but the cell-type expression patterns and intracellular localization of activated, ie, phosphorylated, ERK in the lung after inhalation of asbestos are unclear. C57/BL6 mice were exposed to 7-mg/m(3) air of crocidolite asbestos for 5 and 30 days, the times required for the development of epithelial cell hyperplasia and fibrotic lesions, respectively. Exposure to asbestos caused striking increases in both unphosphorylated and phosphorylated ERK (p-ERK), which were most marked at 30 days and co-localized in bronchiolar and alveolar epithelial cells using an antibody to cytokeratin. Alveolar macrophages, detected with an anti-macrophage antibody, did not express p-ERK. p-ERK was localized at the apical cell surface of bronchiolar and alveolar type II epithelial cells exposed to asbestos fibers, and was most marked in areas of epithelial hyperplasia in association with fibrotic lesions. Because translocation of p-ERK to the nucleus is associated with activation of early response genes and transcription factors, laser scanning cytometry was used to determine the kinetics of activation and nuclear translocation of p-ERK in an alveolar type II epithelial cell line in vitro after exposure to asbestos or the ERK stimuli, epidermal growth factor, or H(2)O(2). Results showed that cytoplasmic to nuclear translocation of p-ERK occurred in a protracted manner in cells exposed to asbestos. The immunolocalization of p-ERK at the membrane surface, a site of initial exposure to asbestos fibers, and the chronic activation of p-ERK in epithelial cells at sites of fibrogenesis are consistent with the concept that epithelial cell signaling through the ERK pathway contributes to remodeling of the lung during the development of pulmonary fibrosis.
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PMID:Persistent localization of activated extracellular signal-regulated kinases (ERK1/2) is epithelial cell-specific in an inhalation model of asbestosis. 1259 5

Although pulmonary fibrosis is a frequent and serious consequence of radiotherapy for thoracic malignant diseases such as lung cancer, the pathogenesis of this radiation-induced lung disorder remains unclear. To clarify the mechanisms underlying radiation pneumonitis and pulmonary fibrosis, we investigated the expression of platelet-derived growth factor receptor (PDGFR) on fibroblasts obtained from irradiated rat lungs and on control fibroblasts. Whole lungs of male Wistar rats were irradiated with a single dose of 15 Gy, and lung fibroblasts were isolated at 4 weeks after the irradiation. The chemotactic response of irradiated lung fibroblasts to PDGF-BB was significantly higher than that of control lung fibroblasts, whereas there was no significant difference between irradiated lung fibroblasts and control lung fibroblasts in the response to PDGF-AA. Receptor binding assay showed more specific binding sites for PDGF-BB on irradiated lung fibroblasts than on control lung fibroblasts, and the displacement of (125)I-labeled PDGF binding to fibroblasts by unlabeled PDGF showed that (125)I-labeled PDGF-BB was displaced by PDGF-BB but not by PDGF-AA. These results suggest that the increased binding sites for PDGF-BB on irradiated lung fibroblasts correspond mainly to PDGFRB. Scatchard analysis of the saturation data demonstrated an approximately twofold increase both in the number of PDGF-BB binding sites and in the binding affinity in irradiated lung fibroblasts compared to that in control lung fibroblasts. Those results suggest that the increased chemotactic response of irradiated lung fibroblasts to PDGF-BB is related to the overexpression of PDGFRB, which may have an important role in the pathogenesis of radiation-induced pneumonitis and pulmonary fibrosis.
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PMID:Increased binding and chemotactic capacities of PDGF-BB on fibroblasts in radiation pneumonitis. 1275 64

Levels of pulmonary and activation-regulated chemokine (PARC) mRNA and protein are increased in the lungs of patients with pulmonary fibrosis. The purpose of this study was to establish whether PARC could be directly involved in development of pulmonary fibrosis by stimulating collagen production in lung fibroblasts. Exposure to PARC increased production of collagen mRNA and protein by 3- to 4-fold in normal adult lung and dermal fibroblast cells. Collagen mRNA transiently increased after 3-6 h of activation with PARC, with an increase in collagen protein detected after 24 h of activation. At the same time, PARC had less pronounced effect on fibroblast proliferation, not exceeding 50% increase over control nonstimulated cells. PARC intracellular signaling led to activation of ERK1/2, but not p38, in fibroblasts; pharmacologic inhibition of ERK, but not p38, also blocked PARC's effect on collagen production. Inhibition experiments with pertussis toxin suggested that PARC receptor is G protein-coupled. Thus, PARC is a member of the CC chemokine family that acts directly as a profibrotic factor.
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PMID:Pulmonary and activation-regulated chemokine stimulates collagen production in lung fibroblasts. 1280 86

Platelet-derived growth factor (PDGF) plays an important role in the pathogenic course of atherosclerosis, pulmonary fibrosis, and glomerulonephritis, and increased activity of the PDGF signaling pathway has been implicated as a contributing factor in the progression of the diseases. Taurine may be a prophylactic amino acid for atherosclerosis not only by decreasing plasma cholesterol level, but also by inhibiting the cell proliferation-signaling pathway. To elucidate how taurine affects the signaling pathway, we investigated the effect of taurine on the expression of immediate-early genes and activation of mitogen-activated protein kinases (MAPKs) in NIH/3T3 cells as standard mesenchymal cells. Taurine inhibited PDGF-BB-induced c-fos and c-jun mRNA expressions dose-dependently, although structural analogues of taurine did not. Taurine decreased the PDGF-induced p44/p42 ERK (extracellular signal-regulated kinase) phosphorylation state dose-dependently, although no phosphorylation was observed on JNK/SAPK (c-Jun N-terminal kinase/stress-activated protein kinase) and p38 MAPK. Further, PDGF-BB-induced tyrosine phosphorylation of the PDGF-beta receptor was not influenced by treatment with taurine, indicating that taurine never affects ligand-receptor interaction, and may act downstream of the PDGF receptor. Thus, the inhibitory mechanism of taurine on PDGF-induced c-fos and c-jun mRNA expressions may depend on the p44/p42 ERK pathway, but not on PDGF-beta receptor tyrosine phosphorylation, JNK/SAPK or p38 MAPK pathway. These results suggest that taurine may suppress the cell proliferation-signaling pathway through the inhibition of ERK activity and immediate-early gene expression.
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PMID:Suppressive effect of taurine on platelet-derived growth factor (PDGF) BB-induced c-fos and c-jun mRNA expressions through extracellular signal-regulated kinase (ERK) in mesenchymal cell lines. 1295 97

The endothelins are a family of endothelium-derived peptides that possess a variety of biological activities, including potent vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and pulmonary fibrosis. Here, we use genome-wide expression array analysis to show that the addition of ET-1 (100 nm, 4 h) to normal lung fibroblasts directly induces expression of matrix and matrix-associated genes, including the profibrotic protein CCN2 (connective tissue growth factor, or CTGF). ET-1 induces the MEK/ERK MAP kinase pathway in fibroblasts. Blockade of the MEK/ERK kinase pathway with U0126 abrogates the ability of ET-1 to induce expression of matrix and matrix-associated mRNAs and the CCN2 protein. The CCN2 promoter possesses an ET-1 response element, which maps to the previously identified basal control element-1 (BCE-1) site. Our results suggest that ET-1 induces a program of matrix synthesis in lung fibroblasts and that ET-1 may play a key role in connective tissue deposition during wound repair and in pulmonary fibrosis.
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PMID:Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. 1504 79

PDGF and its receptors are involved in a variety of diseases: cancers, atherosclerosis, balloon injury induced restenosis, pulmonary fibrosis and more. In all cases enhanced signaling of the receptor is the hallmark. In some cases, like chronic monomyelocytic leukemia (CMML), the persistent PDGFR signaling is essential for the survival of the cancer cell. These findings induced the research community as well as the pharmaceutical industry to develop agents that block PDGFR signaling. The possible utilization of PDGFR kinase inhibitors as anti-restenosis agents is likely to move ahead of the utilization of these agents to treat human malignancies.
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PMID:PDGF receptor kinase inhibitors for the treatment of PDGF driven diseases. 1520 14

Idiopathic pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Prior efforts to treat idiopathic pulmonary fibrosis that focused on anti-inflammatory therapy have not proven to be effective. Recent insight suggests that the pathogenesis is mediated through foci of dysregulated fibroblasts driven by profibrotic cytokine signaling. TGF-beta and PDGF are 2 of the most potent of these cytokines. In the current study, we investigated the role of TGF-beta-induced fibrosis mediated by activation of the Abelson (Abl) tyrosine kinase. Our data indicate that fibroblasts respond to TGF-beta by stimulating c-Abl kinase activity independently of Smad2/3 phosphorylation or PDGFR activation. Moreover, inhibition of c-Abl by imatinib prevented TGF-beta-induced ECM gene expression, morphologic transformation, and cell proliferation independently of any effect on Smad signaling. Further, using a mouse model of bleomycin-induced pulmonary fibrosis, we found a significant inhibition of lung fibrosis by imatinib. Thus, Abl family members represent common targets for the modulation of profibrotic cytokine signaling.
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PMID:Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. 1552 Aug 63


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