UMLS:C0034069 - FACTA Search

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Query: UMLS:C0034069 (pulmonary fibrosis)
7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

The roles of MEK, ERK, the epsilon and alpha isoforms of protein kinase C (PKC), and caveolin-1 in regulating collagen expression were studied in normal lung fibroblasts. Knocking down caveolin-1 gave particularly striking results. A 70% decrease caused a 5-fold increase in MEK/ERK activation and collagen expression. The combined data reveal a branched signaling pathway. In its central portion MEK activates ERK, leading to increased collagen expression. Two branches converge on MEK/ERK. In one, increased PKCepsilon leads to MEK/ERK activation. In another, increased PKCalpha induces caveolin-1 expression, which in turn inhibits MEK/ERK activation and collagen expression. Lung fibroblasts from scleroderma patients with pulmonary fibrosis showed altered signaling. Consistent with their overexpression of collagen, scleroderma lung fibroblasts contain more activated MEK/ERK and less caveolin-1 than normal lung fibroblasts. Because cutaneous fibrosis is the hallmark of scleroderma, we also studied dermal fibroblasts. As in lung, there was more activated MEK/ERK in cells from scleroderma patients than in control cells, and MEK inhibition decreased collagen expression. However, the distinctive levels of PKCepsilon, PKCalpha, and caveolin-1 in lung and dermal fibroblasts from scleroderma patients and control subjects indicate that the links between these signaling proteins and MEK/ERK must function differently in the four cell types. Finally, we confirmed the relevance of these signaling cascades in vivo. The combined results demonstrate that a branched signaling pathway involving MEK, ERK, PKCepsilon, PKCalpha, and caveolin-1 regulates collagen expression in normal lung tissue and is perturbed during fibrosis.
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PMID:Opposing effects of protein kinase Calpha and protein kinase Cepsilon on collagen expression by human lung fibroblasts are mediated via MEK/ERK and caveolin-1 signaling. 1569 37

Interleukin-1beta (IL-1beta) mediates destruction of matrix collagens in diverse inflammatory diseases including arthritis, periodontitis, and pulmonary fibrosis by activating fibroblasts, cells that interact with matrix proteins through integrin-based adhesions. In vitro, IL-1beta signaling is modulated by focal adhesions, supramolecular protein complexes that are enriched with tyrosine kinases and phosphatases. We assessed the importance of tyrosine phosphatases in regulating cell-matrix interactions and IL-1beta signaling. In human gingival fibroblasts plated on fibronectin, IL-1beta enhanced the maturation of focal adhesions as defined by morphology and enrichment with paxillin and alpha-actinin. IL-1beta also induced activation of ERK and recruitment of phospho-ERK to focal complexes/adhesions. Treatment with the potent tyrosine phosphatase inhibitor pervanadate, in the absence of IL-1beta, recapitulated many of these responses indicating the importance of tyrosine phosphatases. Immunoblotting of collagen bead-associated complexes revealed that the tyrosine phosphatase, SHP-2, was also enriched in focal complexes/adhesions. Depletion of SHP-2 by siRNA or by homologous recombination markedly altered IL-1beta-induced ERK activation and maturation of focal adhesions. IL-1beta-induced tyrosine phosphorylation of SHP-2 on residue Y542 promoted focal adhesion maturation. Association of Gab1 with SHP-2 in focal adhesions correlated temporally with activation of ERK and was abrogated in cells expressing mutant (Y542F) SHP-2. We conclude that IL-1beta mediated maturation of focal adhesions is dependent on tyrosine phosphorylation of SHP-2 at Y542, leading to recruitment of Gab1, a process that may influence the downstream activation of ERK.
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PMID:Tyrosine phosphatase SHP-2 regulates IL-1 signaling in fibroblasts through focal adhesions. 1625 12

In cell cultures of human lung fibroblasts, we found that oxidized LDL (oxLDL), after 24-h treatment, stimulated arachidonic acid release. A putative role for phospholipases A(2) and MAPK activities in this process was postulated. Consequently, we studied the contribution of either Ca(2+)-dependent, cytosolic phospholipase A(2) (cPLA(2)) or Ca(2+)-independent phospholipase A(2) (iPLA(2)), and the role of the MAP kinase family in oxLDL toxicity to fibroblastic cells in vitro. Activation of extracellular signal-regulated kinases ERK1/2, p38 and c-Jun NH(2)-terminal kinase (JNK) was also assessed with Western blotting. Compared with cellular samples untreated or treated with native LDL, treatment with oxLDL (50-100 microM hydroperoxides) for 24 h significantly increased the levels of either cPLA(2) protein expression or constitutively phosphorylated cPLA(2) protein; in addition we observed enzyme translocation to membranes. iPLA(2) activity was not stimulated by oxLDL. Arachidonic acid release appeared to be associated with phosphorylation of ERK1/2 which was significantly enhanced in a dose-dependent manner whereas no activation of p38 and JNKs was found, indicating that these MAPKs are not involved in mediating the maximal oxLDL response. Western blotting on subcellular fractions and confocal microscopy analyses confirmed an increase in 15-lipoxygenase (15-LO) protein expression and translocation upon activation. A significant increase of cyclooxygenase-2 expression into membrane fraction was also found. Collectively, the data presented link the stimulation of ERK-cPLA(2)-15-LO pathway by oxLDL to the prooxidant mechanism of the lipoprotein complex. It may initially stimulate the fibroblast reaction against the oxidation challenge as well as metabolic repair, such as during lung inflammation and pulmonary fibrosis.
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PMID:Activation of cytosolic phospholipase A2 and 15-lipoxygenase by oxidized low-density lipoproteins in cultured human lung fibroblasts. 1734 94

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

Lung fibrosis involves the overexpression of ECM proteins, primarily collagen, by alpha-smooth muscle actin (ASMA)-positive cells. Caveolin-1 is a master regulator of collagen expression by cultured lung fibroblasts and of lung fibrosis in vivo. A peptide equivalent to the caveolin-1 scaffolding domain (CSD peptide) inhibits collagen and tenascin-C expression by normal lung fibroblasts (NLF) and fibroblasts from the fibrotic lungs of scleroderma patients (SLF). CSD peptide inhibits ASMA expression in SLF but not NLF. Similar inhibition of collagen, tenascin-C, and ASMA expression was also observed when caveolin-1 expression was upregulated using adenovirus. These observations suggest that the low caveolin-1 levels in SLF cause their overexpression of collagen, tenascin-C, and ASMA. In mechanistic studies, MEK, ERK, JNK, and Akt were hyperactivated in SLF, and CSD peptide inhibited their activation and altered their subcellular localization. These studies and experiments using kinase inhibitors suggest many differences between NLF and SLF in signaling cascades. To validate these data, we determined that the alterations in signaling molecule activation observed in SLF also occur in fibrotic lung tissue from scleroderma patients and in mice with bleomycin-induced lung fibrosis. Finally, we demonstrated that systemic administration of CSD peptide to bleomycin-treated mice blocks epithelial cell apoptosis, inflammatory cell infiltration, and changes in tissue morphology as well as signaling molecule activation and collagen, tenascin-C, and ASMA expression associated with lung fibrosis. CSD peptide may be a prototype for novel treatments for human lung fibrosis that act, in part, by inhibiting the expression of ASMA and ECM proteins.
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PMID:Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo. 1820 15

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