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

Expression microarrays are a powerful tool that could provide new information about the molecular pathways regulating common lung diseases. To exemplify how this tool can be useful, selected examples of informative experiments are reviewed. In studies relevant to asthma, the cytokine interleukin-13 has been shown to produce many of the phenotypic features of this disease, but the cellular targets in the airways and the molecular pathways activated are largely unknown. We have used microarrays to begin to dissect the different transcriptional responses of primary lung cells to this cytokine. In experiments designed to identify global transcriptional programs responsible for regulating lung inflammation and pulmonary fibrosis, we performed microarray experiments on lung tissue from wild-type mice and mice lacking a member of the integrin family know to be involved in activation of latent transforming growth factor (TGF)-beta. In addition to identifying distinct cluster of genes involved in each of these processes, these studies led to the identification of novel pathways by which TGF-beta can regulate acute lung injury and emphysema. Together, these examples demonstrate how careful application and thorough analysis of expression microarrays can facilitate the discovery of novel molecular targets for intervening in common lung diseases.
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PMID:Roger S. Mitchell lecture. Uses of expression microarrays in studies of pulmonary fibrosis, asthma, acute lung injury, and emphysema. 1189 58

Based on studies by our group and others, we hypothesized that IL-7 may possess antifibrotic activities in an IFN-gamma-dependent and independent manner. Here, we have evaluated the antifibrotic therapeutic potential of IL-7 in both in vitro and in vivo pulmonary fibrosis models. IL-7 inhibited both TGF-beta production and signaling in fibroblasts and required an intact JAK1/STAT1 signal transduction pathway. IL-7-mediated inhibition of TGF-beta signaling was found to be associated with an increase in Smad7, a major inhibitory regulator in the SMAD family. In the presence of IL-7, Smad7 dominant negative fibroblasts restored TGF-beta-induced collagen synthesis, indicating that an IL-7-mediated increase in Smad7 suppressed TGF-beta signaling. Consistent with these in vitro findings, recombinant IL-7 decreased bleomycin-induced pulmonary fibrosis in vivo, independent of IFN-gamma. The antifibrotic activities of IL-7 merit further basic and clinical investigation for the treatment of pulmonary fibrosis.
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PMID:IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis. 1192 20

In a rat model of lung injury induced by the antineoplastic antibiotic, bleomycin, there is loss of type I alveolar epithelial cells (AECs) followed by infiltration of activated inflammatory cells, type II AEC proliferation, and fibrosis. At 4 and 7 days after bleomycin administration alveolar macrophages have increased production and release of active transforming growth factor (TGF)-beta1, an inhibitor of epithelial cell proliferation. Paradoxically at these same time intervals there is a concomitant induction of type II AEC proliferation. For TGF-beta-mediated signal transduction to occur, the expression of both TCF-beta receptor types I (TbetaR-I) and II (TbetaR-II) must be present. Using immunohistochemistry and in situ hybridization, 4 and 7 days after bleomycin administration the expression of TbetaR-I on AECs was reduced whereas that of TbetaR-II was unaltered. However, 14 and 28 days after bleomycin injury, when there is decreased proliferation and induction of differentiation of type II AECs, there was a return of TbetaR-I expression on AECs. In contrast, TbetaR-I and TbetaR-II were observed on interstitial fibroblasts at all time intervals after bleomycin administration. Because both TbetaR-I and TbetaR-II are required for signal transduction, the reduction of TbetaR-I levels on the alveolar epithelium may alter the sensitivity of AECs to the antiproliferative effects of TGF-beta1 present in increased quantities following bleomycin injury. The loss of an antiproliferative response to TGF-beta1 may be important for the regeneration of the alveolar epithelium by proliferation while the expression of both receptors onfibroblasts would result in TGF-1 signaling for the synthesis of connective tissue proteins. Ourfindings suggest that during bleomycin-induced pulmonary fibrosis, the effects of TGF-beta1 on cells may be regulated by the expression of TbetaRs.
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PMID:Differential expression of transforming growth factor-beta type I and II receptors by pulmonary cells in bleomycin-induced lung injury: correlation with repair and fibrosis. 1193 76

Transforming growth factor-beta 1 (TGF-beta 1) has important roles in lung fibrosis and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary fibrosis. In this study, we show that TGF-beta1 induces apoptosis of primary cultured bronchiolar epithelial cells via caspase-3 activation and down-regulation of cyclin-dependent kinase inhibitor p21. Concentrations of TGF-beta 1 that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas Ab or rFas ligand-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble Fas ligand in the bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-beta Ab. Otherwise, BALF from patients with hypersensitivity pneumonitis (HP) could not induce apoptosis on bronchiolar epithelial cells, despite its comparable amounts of soluble Fas ligand. The concentrations of TGF-beta 1 in BALF from patients with IPF were significantly higher compared with those in BALF from patients with HP or controls. Furthermore, coincubation with the low concentration of TGF-beta 1 and HP BALF created proapoptotic effects comparable with the IPF BALF. In vivo, the administration of TGF-beta 1 could enhance Fas-mediated epithelial cell apoptosis and lung injury via caspase-3 activation in mice. Our results demonstrate a novel role of TGF-beta 1 in the pathophysiology of pulmonary fibrosis as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
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PMID:TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. 1205 67

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

Bleomycin (BM)-induced pulmonary fibrosis involves excess production of proteoglycans (PGs). Because transforming growth factor-beta(1) (TGF-beta(1)) promotes fibrosis, and interferon-gamma (IFN-gamma) inhibits it, we hypothesized that TGF-beta(1) treatment would upregulate PG production in fibrotic lung fibroblasts, and IFN-gamma would abrogate this effect. Primary lung fibroblast cultures were established from rats 14 days after intratracheal instillation of saline (control) or BM (1.5 units). PGs were extracted and subjected to Western blot analysis. Bleomycin-exposed lung fibroblasts (BLF) exhibited increased production of versican (VS), heparan sulfate proteoglycan (HSPG), and biglycan (BG) compared with normal lung fibroblasts (NLF). Compared with NLF, BLF released significantly increased amounts of TGF-beta(1). TGF-beta(1) (5 ng/ml for 48 h) upregulated PG expression in both BLF and NLF. Incubation of BLF with anti-TGF-beta antibody (1, 5, and 10 microg/ml) inhibited PG expression in a dose-dependent manner. Treatment of BLF with IFN-gamma (500 U. ml(-1) x 48 h) reduced VS, HSPG, and BG expression. Furthermore, IFN-gamma inhibited TGF-beta(1)-induced increases in PG expression by these fibroblasts. Activation of fibroblasts by TGF-beta(1) promotes abnormal deposition of PGs in fibrotic lungs; downregulation of TGF-beta(1) by IFN-gamma may have potential therapeutic benefits in this disease.
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PMID:Proteoglycan expression in bleomycin lung fibroblasts: role of transforming growth factor-beta(1) and interferon-gamma. 1222 58

Pulmonary fibrosis (PF) is caused by a number of inhaled agents, as well as by some drugs and toxic particles. The elaboration of certain peptide growth factors is thought to be key to the development of this disease process. In addition, genetic susceptibility plays a role in the development of PF. For instance, we have previously shown that the 129J strain of mice is resistant, whereas the C57BL/6 strain is highly susceptible, to asbestos-induced fibrosis. To pursue this further, in one mouse model, we crossed the 129J strain to the C57BL/6 strain to produce an F1 generation and subsequently backcrossed the F1 mice to the inbred founders. This backcross to the 129 inbred strain produced reverse similar 25% of the offspring with a phenotype that was protected from the fibrogenic effects of inhaled asbestos fibers. In the second model, both strains of mice were treated intratracheally with an adenovirus vector (AdV), which transduces expression of active transforming growth factor (TGF)-beta(1) in the lungs, producing fibroproliferative lung disease. Compared with C57 mice, a significant number of 129 strain mice exhibited at least a 1-wk delay in the fibroproliferative response to TGF-beta(1) expression at three concentrations of virus. These findings suggest that certain sequences in a gene or a cluster of genes in the 129 mouse strain impart a phenotype in which there is a delay in, or protection from, the development of lung fibrogenesis.
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PMID:Susceptibility to asbestos-induced and transforming growth factor-beta1-induced fibroproliferative lung disease in two strains of mice. 1244 30

Investigators have shown that interstitial pulmonary fibrosis (IPF) can be induced in rats by overexpressing transforming growth factor beta1 (TGF-beta1) through a replication-deficient recombinant adenovirus vector instilled into the lungs (Sime et al. 1997). We have shown that this vector induces IPF in fibrogenic-resistant tumour necrosis factor alpha-receptor knockout (TNF-alphaRKO) mice (Liu et al. 2001). The object of our studies is to understand how peptide growth factors, such as TGF-beta1, mediate interstitial lung disease (ILD). To do so, we must be able to manipulate the dose of the factor and sort out its effects on multiple other mediators in the lung parenchyma. As a step in this complex process, in the studies reported here, we have determined the concentrations of the recombinant adenovirus vector carrying the gene for porcine active TGF-beta1 (AVTGFbeta1) that have little apparent effect, cause clear induction of disease, or severe disease. The disease largely resolves by 28 days in all cases, thus providing a valuable model to understand the mechanisms of the IPF that is mediated, at least in part, by TGF-beta1. The findings here show that 10(6) plaque-forming units (pfu) of AVTGFbeta1, provide essentially a 'no-effect' dose, but even this amount of TGF-beta1 causes a significant increase in whole-lung collagen by day 28 after treatment. In contrast, 10(8) and 10(9) pfu cause severe IPF in 4 days, whereas 10(7) and 5 x 10(7) are intermediate for all parameters studied, i.e. TGF-beta protein, inflammatory cells, cell proliferation, pro-alpha 1(I) collagen gene expression and whole-lung collagen accumulation, and expression of growth factors such as TGF-beta1, TNF-alpha and PDGF-A and -B. Interestingly enough, TGF-beta1, as a potent blocker of epithelial cell proliferation, appears to suppress airway epithelial cell growth that would be expected during the inflammatory phase of IPF. Thus, this model system helps us to understand some quantitative aspects of TGF-beta1 biological activity and allows us to manipulate this potent factor as a mediator of interstitial fibrogenesis.
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PMID:Titration of non-replicating adenovirus as a vector for transducing active TGF-beta1 gene expression causing inflammation and fibrogenesis in the lungs of C57BL/6 mice. 1248 63

TGF-beta is thought to play a central role in pulmonary fibrosis inducing fibroblast differentiation and extracellular matrix synthesis. In human lung fibroblasts, it is still unclear how various TGB-beta isoforms affect TGF-beta production and whether glucocorticoids, commonly used agents to treat fibrotic lung disease, modulate these processes. To this end, human fetal lung fibroblasts (HFL-1) were cultured with various concentrations of glucocorticoids (budesonide, dexamethasone or hydrocortisone) with and without TFG-beta1, -beta2, and -beta3. TGF-beta mRNA was assessed by real time RT-PCR. Smad 2, 3, and 4 and AP-1 complex (c-fos and c-Jun) cellular localization were evaluated by immunostaining. TGF-beta2 and -beta3 stimulated TGF-beta1 production significantly (p < 0.01 relative to control). TGF-beta1 stimulated TGF-beta2 production (p < 0.01 relative to control). TGF-beta3 was undetectable. Glucocorticoids significantly inhibited TGF-beta1 and -beta2 production and reduced expression of the upregulated TGF-beta1 and -beta2 mRNA induced by exogenous TGF-beta1, -beta2 or -beta3 (p < 0.01 for each) but had no effect on Smads. Although c-jun-related nuclear staining was not intensified in TGF-beta-stimulated cells, it was reduced by glucocorticoids. Thus, TGF-beta isoforms may stimulate production of various TGF-beta isoforms in the lung. Glucocorticoids then may block TGF-beta production by modulating mRNA levels and c-Jun.
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PMID:Glucocorticoids modulate TGF-beta production. 1254 37

Pulmonary fibrosis can be observed as an end state in a number of chronic inflammatory pulmonary diseases. Although the mechanisms by which lung fibrosis develops are not fully ascertained, recent findings suggest that oxidative stress may play an important role in the pathogenesis of tissue fibrosis affecting apoptosis of both structural and inflammatory cells and altering the cytokine microenvironment balance. Damage and alteration of alveolar epithelial cells is one of the hallmarks of interstitial lung fibrosis. Recently, it has been demonstrated that the presence of oxidative stress may lead to the damage, activation and/or apoptosis of alveolar epithelial cells either directly, through an imbalanced intracellular redox equilibrium, or indirectly, by activating redox-sensitive effector pathways, such as transcription factors and angiotensin converting enzyme, increasing the conversion of angiotensinogen into angiotensin II that can be considered a mediator of oxidative stress, capable of inducing apoptosis. Furthermore, it has been demonstrated that angiotensin II acts as a proinflammatory cytokine and is effective in activating fibroblasts through the release of transforming growth factor (TGF-beta). As well as activation, differentiation, proliferation and apoptosis of fibroblasts seem related to the oxidant/antioxidant balance, and the maintenance of a high intracellular level of reduced glutathione (GSH) is considered crucial in providing a reducing environment within the cell, able to protect against oxidative stress. In those conditions where oxidants, either inhaled or produced by inflammatory cell, increase, the ratio between GSH and oxidized glutathione (GSSH) may lower, influencing a variety of cellular redox-sensitive signaling processes such as the activation of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) that lead to a transcriptional up-regulation of a number of genes involved in inflammation and/or fibrogenesis, including cytokines [interleukin (IL)-1,, tumor necrosis factor (TNF-alpha), IL-6] chemokines (IL-8), adhesion molecules (VCAM-1, ICAM-1) and growth factors (GM-CSF). In addition, several studies have shown that oxidative stress may also affect the immune response by inducing an up-regulation of HLA-DR as well as the expression of two costimulatory molecules such as CD40 and CD86, determining a persistent state of immune activation, and affecting the Th1/Th2 balance, modulating the T-cell effector response towards the Th2 phenotype. It is clear that a better understanding of the precise sequence of events that make the difference between normal tissue repair and fibrosis, including the role played by oxidative stress, will certainly improve our therapeutic approach to pulmonary fibrosis.
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PMID:Role of oxidative stress in pulmonary fibrosis. 1261 77


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