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 induction of pulmonary alveolar macrophage (PAM) tissue factor-dependent procoagulant activity is central to the deposition of inflammatory fibrin in the pulmonary alveolus. The presence of enhanced tissue factor activity is often associated with pulmonary fibrin deposition, an important pathogenetic event that can delay resolution of pulmonary inflammation and promote the induction of pulmonary fibrosis. Since tissue factor synthesis induction and activation pathways are potential therapeutic targets for modulation of alveolar macrophage tissue factor (procoagulant) activity, we examined the pathways through which endotoxin lipopolysaccharide (LPS) induces bovine PAM tissue factor-dependent procoagulant activity. PAM procoagulant activity was markedly enhanced to 10 times the levels of freshly isolated PAM after 8 h of culture in the presence of either the protein kinase C (PKC) agonist phorbol 12-myristate 13-acetate (PMA) or LPS. Both LPS-(P less than 0.002) and PMA-induced activity (P less than 0.007) was completely ablated by the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H 7,100 microM) but was unaffected by the cyclic nucleotide-dependent protein kinase inhibitor N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004, 100 microM). The arachidonate cyclooxygenase pathway inhibitor phenylbutazone (10(-4) M) had modest effects that were not statistically significant. The unstimulated increase of procoagulant activity in 8-h cultures was unaffected by the same inhibitory modulations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endotoxin-mediated bovine alveolar macrophage procoagulant induction is dependent on protein kinase C activation. 209 May 87

Extensive tissue remodeling occurs in survivors of acute lung injury, leading to nearly normal histology and physiology in the majority of individuals, whereas others suffer significant impairment due to the development of pulmonary fibrosis. Alveolar epithelial cells play a central role in the repair process. They are strategically located to directly participate in the solubilization of intraalveolar fibrin deposits, and have the capacity to promote fibrinolysis. We have previously reported that interleukin-1 beta (IL-1 beta), an important inflammatory mediator in acute lung injury, upregulates urokinase-type plasminogen activator expression by human A549 cells (1). In this work, we show that IL-1 beta increases cell-surface plasmin generation, mediated in part by increased expression of urokinase receptor (u-PAR). Northern blot analyses demonstrated that IL-1 beta rapidly induces accumulation of u-PAR messenger RNA (mRNA) in a dose-dependent fashion, and that this effect is blocked by actinomycin. The IL-1 beta-mediated increase in u-PAR mRNA is inhibited by: (1) the relatively specific protein kinase C (PKC) inhibitors 1-(5-isoquinoline sulfonyl)-2-methylpiperazine (H7) and calphostin C; and (2) prolonged pretreatment of cells with phorbol myristate acetate (PMA), suggesting that PKC is an important component of the signaling pathway. Okadaic acid, an inhibitor of serine/threonine phosphatases, markedly potentiates the effect of IL-1 beta on u-PAR mRNA levels. In contrast, dexamethasone, in concentrations as low as 10(-8) M, completely blocks the IL-1 beta-mediated increase in u-PAR mRNA. Half-life experiments show that dexamethasone has no effect on u-PAR mRNA stability. Aldosterone, at concentrations in which it binds primarily to the mineralocorticoid receptor, has no effect on u-PAR expression, suggesting that the glucocorticoid effect is due to a transrepressive mechanism. In summary, IL-1 beta increases cell-surface plasmin generation in A549 cells by coordinately upregulating urokinase and u-PAR expression. Transcriptional activation of the u-PAR gene involves PKC-dependent mechanisms, and glucocorticoid suppression is probably due to interactions between the glucocorticoid receptor and another transcriptional activating system such as activator protein-1 (AP-1) and/or nuclear factor-kB (NF-kB).
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PMID:Induction of urokinase-type plasminogen activator receptor by IL-1 beta. 919 70

Asbestos and the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), increase c-fos and c-jun mRNA levels and AP-1 DNA binding activity in rat pleural mesothelial (RPM) cells, a target cell of asbestos-induced mesotheliomas (N. H. Heintz et al., Proc. Natl. Acad. Sci. USA, 90: 3299-3303, 1993). Because protein kinase C (PKC) is the intracellular receptor of phorbol ester tumor promoters and asbestos is a putative tumor promoter in the respiratory tract, we hypothesized that PKC might play a critical role in asbestos-induced cell signaling pathways associated with regulation of proto-oncogenes. Using a panel of PKC antibodies, we identified PKC alpha as the major PKC isozyme in RPM cells. We then pretreated cells with phorbol ester dibutyrate to down-modulate PKC or with calphostin C, a specific PKC inhibitor, to determine if depletion of PKC alpha could block asbestos-induced c-fos/c-jun expression. Quantitation of Northern blots showed that fiber-associated c-fos/c-jun mRNA levels were significantly lower either after PKC alpha down-modulation or pretreatment with calphostin C. In addition, to determine whether tyrosine kinases also were involved in proto-oncogene activation by asbestos, tyrphostin AG82 or herbimycin A was added to RPM cells before exposure to asbestos. These inhibitors decreased crocidolite-induced c-fos but not c-jun levels, suggesting that tyrosine kinases have different regulatory roles in asbestos-induced c-fos versus c-jun signaling pathways. The ability to block induction of asbestos-induced proto-oncogene expression using pharmacological intervention may be important in prevention and treatment of asbestos-induced proliferative diseases including lung cancers, mesothelioma, and pulmonary fibrosis.
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PMID:Inhibition of protein kinase C prevents asbestos-induced c-fos and c-jun proto-oncogene expression in mesothelial cells. 924 32

Silica is a well-known occupational fibrogenic agent and its primary target cell is alveolar macrophage. Particle-stimulated macrophages are believed to release various mediator which can regulate the inflammation as well as pulmonary fibrosis. Even though oxygen radicals play the major role among these mediators, the mechanisms concerning the stimulation of alveolar macrophages are not clear yet. The present study was carried out to investigate the signal transduction pathway on oxygen radical generation in silica-stimulated alveolar macrophages. Silica induced oxygen radical generation in a dose-response pattern. Extracellular calcium depletion, calcium channel blockers, and calcium release blocker decreased the effect of silica on oxygen radical generation. Silica increased intracellular calcium through the influx of calcium through the calcium channel and the calcium release from the intracellular calcium store. To know the role of protein kinase C (PKC), phospholipase C (PLC), and protein tyrosine kinase (PTK) in silica-induced oxygen radical generation, we pretreated alveolar macrophages with inhibitors of these enzymes. Inhibitors of PKC (sphingosine and staurosporine), PLC (neomycin and U-73122), and PTK (genistein and erbstatin) suppressed the silica-induced oxygen radical generation. Silica increased the PLC activity at the concentration of 5 mg/ml. The inhibitors of PTK and PLC suppressed the action of silica on the PLC activity. From these results, we suggest that silica induces oxygen radical generation through PTK, PLC, and PKC in alveolar macrophages.
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PMID:Silica-induced oxygen radical generation in alveolar macrophage. 924 22

Positive-pressure mechanical ventilation can injure the lung, causing edema and alveolar inflammation in a complication termed ventilator-induced lung injury (VILI). Cytokines such as interleukin-8 (IL-8) reportedly are important in this inflammatory response. On the other hand, hepatocyte growth factor (HGF) promotes regeneration of the lung, and delays pulmonary fibrosis. We postulated that cyclic stretch upregulates production and release of both of mediators. Human alveolar epithelial cells (A549) cultured on a silicoelastic membrane were tested for mRNA expression and release of IL-8 and HGF after cyclic stretch in vitro. Stretch induced mRNA expression and release of these mediators. The signaling pathway from cyclic stretch to release of IL-8 and HGF appeared to involve protein kinase C in the signal transduction pathway.
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PMID:Stretch induces a growth factor in alveolar cells via protein kinase. 1150 83

Myofibroblasts, characterised by high expression of alpha-smooth muscle actin (alpha-SMA), are important and transient cells in normal wound healing but are found in increased number in various pathological conditions of the lung including asthma and pulmonary fibrosis. The mechanisms that regulate the myofibroblast phenotype are unknown but are likely to involve signals from the extracellular matrix transmitted via specific integrins. Vitronectin is a glycoprotein released during inflammation and has been shown to regulate the phenotype of vascular smooth muscle cells via alpha v and beta 1 integrins. In the current study we have examined whether vitronectin influences the phenotype and function of normal human lung fibroblasts (HFL-1). Incubation of HFL-1 cells with vitronectin induced a concentration-dependent reduction in alpha-SMA expression. By contrast, function-blocking monoclonal antibodies to the vitronectin integrins alpha v, beta 1, alpha v beta 3 and alpha v beta 5 induced the expression of alpha-SMA and its organization into stress fibers. Expression of alpha-SMA induced by all function-blocking monoclonal antibodies was abrogated by inhibition of protein kinase C and phosphatidylinositol-3 kinase, but the effects of inhibition of other signalling pathways was integrin dependent. Exposure to other extracellular matrix proteins such as fibronectin, collagen or their integrins did not influence expression of alpha-SMA. The expression and organization of alpha-SMA induced by exposure to function-blocking antibodies was translated into an augmented capacity of HFL-1 cells to contract fibroblast populated collagen gels. By contrast, contraction of collagen gels following incubation with vitronectin was not significantly different to control. This study has shown that vitronectin influences the phenotype and behaviour of HFL-1 cells by downregulating the expression of alpha-SMA and reducing their contractile ability. By contrast, occupancy of specific integrins by function-blocking antibodies upregulated the expression of alpha-SMA and induced the formation of functional stress fibers capable of contracting collagen gels. These results suggest that vitronectin modulates the fibroblast-myofibroblast phenotype, implying an important role in the remodelling process during lung development or response to injury.
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PMID:Regulation of human lung fibroblast phenotype and function by vitronectin and vitronectin integrins. 1168 10

Hepatocyte growth factor (HGF) was purified as a potent mitogen for rat hepatocytes in primary culture and is believed to be the most physiological hepatotrophic factor that triggers liver regeneration. HGF is one of the largest disulfide-linked cytokines, consisting of a 60-kDa heavy chain and a 35-kDa light chain. Human HGF is synthesized as a single polypeptide chain precursor of 728 amino acid residues that has an appreciable homology with plasminogen, and it is processed proteolytically to release an N-terminal signal peptide of 31 amino acids and to generate an active heterodimer after secretion. The novel serine protease HGF activator and urokinase-type plasminogen activator (u-PA) are responsible for the latter extracellular processing. HGF stimulates the proliferation of rat hepatocytes in primary culture at concentrations as low as 10 pM. It also stimulates the growth of various epithelial cells, endothelial cells, and some kinds of mesenchymal cells. HGF inhibits the proliferation of several tumor cell lines and induces apoptosis of some of them. It also has motogenic, morphogenic, anti-apoptotic, angiogenic, and immunoregulatory activities. The receptor of HGF is the product of c-met proto-oncogene with tyrosine kinase activity that mediates the transduction of multiple biological signals of HGF. During liver regeneration, HGF gene expression in the liver, spleen, and lung and HGF levels in the blood and liver increase prior to the induction of liver DNA synthesis. Liver regeneration is markedly inhibited by continuous administration of a neutralizing anti-HGF antibody. HGF production in cultured cells is induced by PKC-activating agents, cAMP-elevating agents, PKA-activating agents, growth factors, and inflammatory cytokines; and it is inhibited by TGF-beta, glucocorticoids, 1,25-dihydroxyvitamin D3, and retinoic acid. There are many reports on potential application of HGF as a therapeutic agent for organ diseases that are difficult to cure such as liver cirrhosis, chronic renal failure, pulmonary fibrosis, myocardial infarction, and arteriosclerosis obliterans utilizing its potent growth-stimulating activity for a wide variety of cells. ELISA kits for assays of serum and plasma HGF levels are clinically used to prognosticate the development of fulminant hepatic failure.
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PMID:[Function and regulation of production of hepatocyte growth factor (HGF)]. 1206 Nov 40

Transforming growth factor-beta (TGF-beta) is a potent fibrogenic factor responsible for promoting synthesis of extracellular matrix. Interleukin-7 (IL-7) inhibits TGF-beta signaling by up-regulating Smad7, a major inhibitor of the Smad family. In a variety of cells, TGF-beta-mediated activation of target genes requires active protein kinase C-delta (PKC-delta) in addition to Smads (1). We determined the role of PKC-delta in the regulation of pulmonary fibroblast collagen synthesis in response to TGF-beta and IL-7 stimulation. Here we show that TGF-beta and IL-7 have opposing effects on PKC-delta; TGF-beta stimulates, while IL-7 inhibits, PKC-delta activity. IL-7 inhibits TGF-beta-induced PKC-delta phosphorylation at Ser-645 and Thr-505. Inhibition of PKC-delta with specific small inhibitory RNA restores TGF-beta-mediated induction of Smad7 and in parallel significantly reduces TGF-beta-mediated collagen synthesis. Thus, PKC-delta may play a critical role in the pathogenesis of pulmonary fibrosis and may serve as a molecular target for therapeutic intervention to suppress fibrosis.
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PMID:Interleukin-7 and transforming growth factor-beta play counter-regulatory roles in protein kinase C-delta-dependent control of fibroblast collagen synthesis in pulmonary fibrosis. 1513 32

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

Integrin signaling plays a critical role in many aspects of normal growth, differentiation, and injury response. In the adult, alpha8beta1 is expressed in alveolar myofibroblasts and is upregulated in pulmonary fibrosis and other models of organ injury. Following injury, survival of fibronectin-producing myofibroblasts cells is an important determinant of development of fibrosis. Using stable alpha8-transfected cell lines, we show that interactions of alpha8beta1 with its ligand, fibronectin, promote cell survival during serum deprivation. Multiple cell signaling pathways were activated following fibronectin adhesion, including PI3 kinase and MAP kinase. However, the alpha8-mediated cell survival was blocked by LY294002, a PI3 kinase inhibitor, but not by staurosporine, a PKC inhibitor, or PD98059, a MAPK kinase inhibitor. A dominant negative construct of PI3 kinase also inhibited alpha8-mediated cell survival. Therefore, alpha8-mediated survival appears to be mediated by the PI3 kinase pathway. Survival of alpha8-expressing myofibroblasts may contribute to persistent fibrosis following injury.
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PMID:Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway. 1572 7


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