Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta (TGF-beta) and interleukin-1 (IL-1) are essential participants in the development of pulmonary fibrosis. Administration of inhibitors to either cytokine can prevent the onset and progression of lung fibrosis in animal models. In this report, stable Thy-1+ and Thy-1- murine lung fibroblast subpopulations were analyzed for expression of the three mammalian TGF-beta isoforms. TGF-beta 1, TGF-beta 2, and TGF-beta 3 mRNA transcripts were detected by reverse transcriptase-PCR in both murine fibroblast subsets. Most of the TGF-beta produced by fibroblasts is latent; however, a small amount of active TGF-beta can be detected using a sensitive mink lung cell bioassay. By incorporating neutralizing anti-TGF-beta isoform-specific antibodies, it was determined that TGF-beta 1 is the predominant isoform present in both the active and the latent forms. Overall, Thy-1- fibroblasts secrete twice as much latent TGF-beta as the Thy-1+ subset. To investigate whether a link exists between TGF-beta and IL-1, the effect of TGF-beta 1 on the expression of IL-1 receptor type I (IL-1RtI) by fibroblast subsets was assessed by flow cytometry and Scatchard analysis. TGF-beta 1 significantly down-regulates the expression of IL-1RtI by Thy-1+ fibroblasts, but not by Thy-1- fibroblasts. A functional consequence of this down-regulation of the IL-1RtI is that it makes Thy-1+ fibroblasts less responsive to IL-1-mediated induction of IL-6 protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of TGF-beta isoforms by Thy-1+ and Thy-1- pulmonary fibroblast subsets: evidence for TGF-beta as a regulator of IL-1-dependent stimulation of IL-6. 785 60

We have investigated the mitogenic and chemotactic role of platelet-derived growth factor (PDGF) in pulmonary fibrogenesis induced by chrysotile asbestos. Since fibroblasts phagocytize asbestos in the lung interstitium, we have sought to learn whether the fibers alter the production of PDGF-like molecules by rat lung fibroblasts or induce mitogenesis of these fibroblasts in vitro. Conditioned medium as well as cell lysates from fibroblasts exposed to asbestos contained approximately 4-fold more PDGF than unexposed cells as detected by Western blot. Two distinct molecular weight forms of PDGF (36 and 18 kD) were detected by Western blotting. We postulate that these PDGF-like molecules are homologues of human PDGF-AA since we could not detect any PDGF in a sensitive enzyme immunoassay that recognized only PDGF-BB and PDGF-AB. Furthermore, PDGF-A chain mRNA was readily detected by Northern analysis, whereas PDGF-B chain mRNA was not detected by conventional Northern analysis. However, message amplification using a reverse transcriptase polymerase chain reaction allowed detection of the B-chain message. A significant dose-dependent mitogenic effect of asbestos was found by using both a cell proliferation assay and nuclear labeling with bromodeoxyuridine when fibroblasts were exposed under serum-free conditions. This mitogenesis induced directly by asbestos was blocked almost entirely with an anti-PDGF antibody that neutralized all three PDGF isoforms. Thus, these data support our hypothesis that an autocrine loop for PDGF-AA is operative in vitro following exposure to asbestos in lung fibroblasts, and we suggest that this signaling pathway could be significant in the pathogenesis of pulmonary fibrosis.
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PMID:Chrysotile asbestos stimulates platelet-derived growth factor-AA production by rat lung fibroblasts in vitro: evidence for an autocrine loop. 786 15

Interleukin-6 (IL-6) is a pleiotropic cytokine having several functions, including the regulation of immunologic and inflammatory responses. It is produced by many cell types, including lymphocytes, macrophages, and fibroblasts, and is believed to play a major role in pulmonary fibrosis, a condition resulting from expansion of the fibroblast compartment and the accumulation of extracellular matrices secreted primarily by fibroblasts. Production of IL-6 by lung fibroblasts has been well documented; however, it was not known whether all murine lung fibroblasts secreted IL-6 or only subsets thereof. Previous studies in our laboratory have shown that murine lung fibroblasts can be divided into subpopulations based on Thy 1 expression. These subpopulations, Thy 1+ and Thy 1-, differ in morphology, expression of surface markers, and function. IL-6 mRNA was detected in both Thy 1+ and Thy 1- murine fibroblasts and clones using reverse transcriptase polymerase chain reaction (RT-PCR). Interestingly, semi-quantitative RT-PCR and Northern blot analysis demonstrated that IL-6 mRNA was down-regulated in confluent fibroblast cultures versus cultures in log phase growth. Also, IL-6 activity was detected in the supernatants of murine lung fibroblast lines and clones using an IL-6-dependent hybridoma assay. Hybridoma proliferation was inhibited by the addition of a neutralizing anti-mouse IL-6 antibody, indicating that the activity was indeed due to IL-6. The lung fibroblasts expressed IL-6 receptors on their surface as determined by flow cytometry using a rat anti-mouse IL-6 receptor antibody (15A7).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-6 is an autocrine growth factor for murine lung fibroblast subsets. 794 84

In the surfactant protein C/tumor necrosis factor (SP-C/TNF) transgenic mouse, the TNF-alpha transgene is overexpressed in type II pneumocytes. Pulmonary lymphocytic infiltration develops which is followed by fibrotic changes including accumulation of fibroblasts and deposition of extracellular matrix. We hypothesized that lymphocytes played a role in the development of pulmonary fibrosis in this model. Lymphocytes were recovered from the interstitium of the lung and analyzed by flow cytometry. The absolute number of lymphocytes recovered from transgenic mice were approximately four times of that in littermates. Flow cytometric analysis showed the presence of gamma delta T cells and B1 cells in the former group but these cells were almost absent in the lung of non-transgenic littermates. We also studied lymphocytes accumulating in the lung during bleomycin (BLM)-induced pneumopathy. Serial analyses showed a progressive increase of CD4/CD8 ratio after injection of BLM, reaching a peak at day 14, then decreased to the normal level by day 48. Northern blot analysis of the lung showed an enhanced expression of interleukin (IL)-2 and osteopontin (OPN) mRNA in those two models of pulmonary fibrosis. Expansion of clonal alpha beta T cells as detected by reverse transcriptase-polymerase chain reaction/single strand conformation polymorphism (RT-PCR/SSCP) suggests involvement of antigen-driven mechanisms in the development of pulmonary fibrosis.
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PMID:Immunophenotyping of lymphocytes in the lung interstitium and expression of osteopontin and interleukin-2 mRNAs in two different murine models of pulmonary fibrosis. 945 69

There are several unsolved clinical findings in patients with idiopathic pulmonary fibrosis (IPF); (i) predominance of fibrosis in the lower lung fields, (ii) digital clubbing, and (iii) patchy distribution of pulmonary fibrosis. To explain these unsolved problems, we hypothesized that regenerated or premature bronchoepithelial cells may circulate in the blood in patients with IPF. To prove this, we performed the reverse transcriptase-polymerase chain reaction (RT-PCR) for cytokeratin 19 (CK19) and pulmonary surfactant protein A (SPA) in peripheral blood in patients with IPF and pulmonary fibrosis associated with collagen vascular disorders. In addition, 20 patients with chronic pulmonary emphysema as a disease control and 19 normal volunteers were also evaluated for the existence of circulating bronchoepithelial cells. RT-PCR analysis showed that CK19 was expressed in 12 of 38 blood samples (31.6%) of IPF and pulmonary fibrosis associated with collagen vascular disorders, seven of 20 (35.0%) blood samples of chronic pulmonary emphysema, and four of 19 (21.1%) blood samples of normal volunteers. mRNA for SPA was positive in eight of 38 (21.1%) blood samples of IPF. In contrast, SPA expressing cells were not detected in any blood samples obtained from patients with chronic pulmonary emphysema or normal volunteers. This evidence suggests that there were some circulating bronchoepithelial cells expressing mRNA for SPA in peripheral blood of patients with IPF and pulmonary fibrosis associated with collagen vascular disorders.
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PMID:Circulating bronchoepithelial cells expressing mRNA for surfactant protein A in patients with pulmonary fibrosis. 1086 11

Bleomycin-induced lung injury causes increased fibroblast numbers in the lung and pulmonary fibrosis. Studies of fibroblasts isolated from such injured lungs have revealed evidence of increased intrinsic proliferative capacity, but the mechanism is unknown. Telomerase catalyzes the addition of telomeric DNA repeats onto chromosomal ends, which is associated with increased cellular life span or immortality. To examine whether telomerase might play a role in regulating fibroblast proliferative capacity in pulmonary fibrosis, lung fibroblasts were isolated from rats treated with endotracheal injections of phosphate-buffered saline or bleomycin. At selected time points, the rats were killed and lung fibroblasts isolated. The isolated cells and lung tissue were then used in experiments for measurement of telomerase activity. The results show undetectable telomerase activity in fibroblasts isolated from control uninjured lungs, or in the control lung tissue extracts. Similar results were obtained in cells and lung tissue from Days 1, 3, and 28 bleomycin-injured lungs. However, significant telomerase activity was detected in fibroblasts and tissue extracts isolated from Days 7, 14, and 21 bleomycin-treated rat lungs, with maximal activity observed in the Day 14 samples. Analysis of the isolated cells for telomerase messenger RNA or reverse transcriptase expression, combined with alpha-smooth-muscle actin expression by immunohistochemistry, revealed that telomerase expression localized primarily to nonmyofibroblasts. These findings suggest that in addition to elevated growth factor expression, the injured lung fibroblast population may contain cells with increased life span, which could contribute to the observed overall increase in lung fibroblast numbers.
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PMID:Induction of telomerase activity in fibroblasts from bleomycin-injured lungs. 1101 10

Interleukin-4 (IL-4) is known to activate mononuclear cells as well as fibroblasts, all of which are important in the pathogenesis of pulmonary fibrosis. To investigate the potential role of this cytokine, lung IL-4 expression was examined in a murine model of bleomycin-induced pulmonary fibrosis. Lung fibrosis was induced in CBA/J mice by endotracheal injection of bleomycin on day 0. On selected days after treatment, lungs were harvested for reverse transcriptase polymerase chain reaction (RT-PCR), Northern, in-situ hybridization and immunohistochemical analyses. RT-PCR and Northern analyses revealed significant increases in lung IL-4 mRNA content between days 3 and 14 after induction of lung injury, which decreased toward control level after day 21. Both in-situ hybridization and immunohistochemistry showed low or undetectable IL-4 expression in control lungs and in injured lungs before day 3 after bleomycin injection. There was however elevated expression in mononuclear cells and macrophages between days 3 and 14, localized to areas of active fibrosis. These results demonstrate that IL-4 is upregulated significantly in this model. They suggest a potential role for this cytokine in pulmonary fibrosis, perhaps via its ability to stimulate and amplify the inflammatory response, stimulate collagen synthesis in fibroblasts, and thus promote the progression to fibrosis and end stage lung disease.
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PMID:Lung interleukin-4 gene expression in a murine model of bleomycin-induced pulmonary fibrosis. 1155 83

Pulmonary fibrosis is a progressive disorder characterized by the loss of alveolar architecture through epithelial and endothelial cell apoptosis and fibroblast proliferation. Recent studies showed that angiotensin-converting enzyme (ACE) activity is increased in fibrotic tissues, and ACE inhibitors administered in vivo ameliorate fibrosis, suggesting that ACE may play a critical role. However, the regulation of ACE expression is not well understood. In the present study, we demonstrate that bleomycin, a chemotherapeutic agent which induces pulmonary fibrosis in animals and humans, increases gene expression of ACE. Treatment of primary bovine pulmonary artery endothelial cells with 0.1 to 1.0 microg/ml bleomycin increased ACE enzymatic activity and ACE mRNA, as monitored by hippuryl-L-histidyl-L-leucine assay and competitive quantitative reverse transcriptase polymerase chain reaction (RT-PCR), respectively. Luciferase reporter constructs showed that upregulation of ACE transcription by bleomycin is mediated through element(s) in the 97-bp ACE promoter. Bleomycin activated p42/p44 mitogen-activated protein kinase (MAPK) and induced nuclear translocation and activation of the early growth response (Egr)-1 transcription factor, a factor previously shown to positively regulate ACE expression. The MAPK kinase1/2 (MEK1/2) inhibitor U0126 blocked MAPK and Egr-1 activation by bleomycin, suggesting that Egr-1 activation is MAPK dependent. These data provide the first evidence that bleomycin activates ACE gene expression through the MAPK pathway and Egr-1.
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PMID:Bleomycin upregulates gene expression of angiotensin-converting enzyme via mitogen-activated protein kinase and early growth response 1 transcription factor. 1171 4

Fibroblasts from bleomycin-injured lungs express telomerase activity transiently during the period of active fibrosis, but the signal(s) responsible for its induction is (are) unknown. The objective of this study was to identify potential mediators capable of regulating telomerase activity induction in rat lung fibroblasts during pulmonary fibrosis. Lung fibroblasts from control (NRF) and bleomycin-treated (BRF) rats were isolated and treated in vitro with either basic fibroblast growth factor (bFGF) or interleukin-4 (IL-4). At selected time points after treatment, the cells were analyzed for telomerase activity, as well as telomerase reverse transcriptase (TERT) mRNA and protein by reverse transcriptase/polymerase chain reaction and Western blot, respectively. The results showed that bFGF could induce telomerase activity in NRF and stimulate further the induced activity in BRF. The bFGF effect was accompanied by increased TERT protein expression and a rapid but transient increase in TERT mRNA. In contrast, IL-4 inhibited the induced telomerase activity in BRF, which was accompanied by increased alpha-smooth muscle actin expression, an indicator of myofibroblast differentiation. These findings suggest that telomerase expression could be induced in rat lung fibroblasts by bFGF, but suppressed by IL-4, which promoted myofibroblast differentiation. The latter is consistent with the preferential expression of telomerase activity in fibroblasts relative to myofibroblasts.
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PMID:Regulation of telomerase activity in rat lung fibroblasts. 1197 Sep 2

Serum response factor (SRF) is a transcription factor essential for smooth muscle (SM) myogenesis. Its role in myofibroblast differentiation is, however, unknown. We studied the expression and the localization of SRF in bleomycin-induced pulmonary fibrosis, where myofibroblasts are abundant. We found that SRF levels were upregulated in bleomycin-exposed mouse lungs mainly due to de novo synthesis of SRFDelta5, a less myogenic SRF isoform. Before myofibroblast differentiation, SRF/SRFDelta5 was immunolocalized mostly in the cytoplasm of scattered fibroblasts at lesion sites. With the development of myofibroblasts, however, SRF/SRFDelta5 was found in myofibroblast nuclei. cDNA array analysis showed that SRFDelta5 and SRF induced expression of transforming growth factor-beta1, a critical factor in myofibroblast differentiation. This was accompanied by de novo expression of several inflammatory cell-specific mRNAs. The latter was confirmed by reverse transcriptase-polymerase chain reaction. Treatment of lung fibroblasts with tumor necrosis factor-alpha, which is produced early in the bleomycin model, induced SRFDelta5 expression and SRF/SRFDelta5 cytoplasmic accumulation, whereas addition of transforming growth factor-beta1 caused SRF/SRFDelta5 nuclear translocation followed by SM alpha-actin synthesis. Interleukin-4, another cytokine involved in myofibroblast differentiation, did not affect SRF or induce SRFDelta5 expression. Our studies therefore suggested a new mechanism whereby SRF and SRFDelta5 contribute to the emergence of myofibroblasts in lung injury and fibrosis.
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PMID:Involvement of serum response factor isoforms in myofibroblast differentiation during bleomycin-induced lung injury. 1277 47


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