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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Collagen deposition and myofibroblast proliferation beneath the epithelial basement membrane in patients with asthma is now increasingly recognized, although the molecular pathogenesis remains obscure. We have evaluated messenger ribonucleic acid (mRNA) expression of the profibrotic cytokine, platelet-derived growth factor-beta (PDGF-beta), in alveolar macrophages obtained following fibreoptic bronchoscopy and bronchoalveolar lavage in patients with asthma. Three subject groups were studied: 1) asthmatics using regular inhaled glucocorticoid medication (ASTST, n = 9), 2) asthmatics using intermittent inhaled beta 2-agonist therapy only (ASTBR, n = 10); 3) nonasthmatic control volunteers (n = 10). Alveolar macrophage mRNA was extracted and PDGF-beta mRNA quantified by reverse-transcriptase polymerase chain reaction (PCR) (RT-PCR) and expressed as the ratio to that of a control gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). There were no significant differences in PDGF-beta mRNA expression between the groups, or between all asthmatic (n = 19) and control subjects. Furthermore, there was no correlation between alveolar macrophage PDGF-beta mRNA expression and airway spirometry, or duration of glucocorticoid usage or dose. Thus, in contrast to other fibrotic lung diseases, we found little evidence of enhanced expression of PDGF-beta mRNA in alveolar macrophages in clinically stable bronchial asthma.
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PMID:Platelet-derived growth factor-beta mRNA in human alveolar macrophages in vivo in asthma. 787 66

Asthma has been reported to be associated with a reduction in the activity of glutathione peroxidase (GSH-Px), an important antioxidant enzyme. However, the expression of GSH-Px enzyme activity has not previously been investigated in human eosinophils, which are important inflammatory cells involved in asthma. Reverse transcriptase-polymerase chain reaction and Southern blotting demonstrated that eosinophils express GSH-Px mRNA and the relative expression of GSH-Px was greater in eosinophils than in neutrophils for both asthmatic and non-asthmatic subjects. The presence of GSH-Px protein in eosinophil and neutrophil lysates was confirmed by size exclusion chromatography and by Western blotting. GSH-Px enzyme activity as measured by a spectrophotometric assay was greater in eosinophil (48.4+/-1.6 micromol NADPH oxidized x min(-1) x g(-1) protein) than in neutrophil lysates (18.1+/-0.4, n = 24, P < 0.0001). GSH-Px activities of eosinophils and neutrophils from asthmatic subjects did not differ from those of non-asthmatic subjects. Eosinophil GSH-Px activity was correlated with peripheral blood eosinophil count only in asthmatic subjects (rs = 0.59, n = 12, P = 0.04). Increased GSH-Px expression in eosinophils compared with neutrophils of asthmatic patients may provide antioxidant protection against the greater amounts of reactive oxygen species generated by these cells and may enhance the survival of eosinophils at sites of inflammation in asthma.
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PMID:Glutathione peroxidase activity and mRNA expression in eosinophils and neutrophils of asthmatic and non-asthmatic subjects. 946 82

Human bronchial smooth muscle (HBSM) contraction is implicated in a variety of respiratory diseases, including asthma. Yet, the presence of an operative calcium-induced calcium release (CICR) mechanism, identified in various smooth muscles, has not been established in HBSM. We therefore studied Ca-releasing mechanisms in HBSM obtained at thoracotomy with special attention to ryanodine-sensitive receptor channels (RyRs). In freshly isolated bronchial myocytes, ryanodine (0.5 to 50 microM) and caffeine (1 to 25 mM) induced transient increases in the cytoplasmic calcium concentration ([Ca(2+)](i)). Higher ryanodine concentrations (> 100 microM) inhibited the caffeine-induced [Ca(2+)](i) response, which was also blocked in the presence of tetracaine (300 microM) or ruthenium red (200 microM), two potent CICR inhibitors. In HBSM strips, caffeine induced a transient contraction which, likewise, was inhibited by ryanodine and tetracaine. However, ryanodine (200 microM) modified neither the [Ca(2+)](i) response nor the contraction induced by K(+)-rich (110 mM) solution. Reverse transcriptase/polymerase chain reaction (RT-PCR) and RNase protection assay performed in HBSM have revealed the existence of mRNAs encoding only the type 3 RyR. We also characterized acetylcholine-induced [Ca(2+)](i) and contractile responses. None of these responses was altered by ryanodine or by tetracaine. These results demonstrate, for the first time, the existence of functional RyRs in HBSM cells which, owing to the type of isoform or the amount of protein expressed, are not involved, under physiologic conditions, in depolarization- or agonist-induced contraction.
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PMID:Human isolated bronchial smooth muscle contains functional ryanodine/caffeine-sensitive Ca-release channels. 1093 7

CC chemokine receptors are expressed on hematopoietic cells, and these may impart selective homing of monocyte, leukocyte, and lymphocyte subsets to sites of inflammation. CC chemokine receptor 3 is the major receptor on eosinophils and is also expressed on other inflammatory cells suggesting its important role for allergic diseases such as atopic dermatitis and bronchial asthma. Eotaxin, eotaxin-2 and eotaxin-3 have been identified as ligands that only activate CC chemokine receptor 3. CC chemokine receptor 3 is also activated by other promiscuous ligands, however, such as RANTES and monocyte chemotactic protein 4. To date, CC chemokine receptor 3 has not been reported to be expressed on nonhematopoietic cells. In this study, we investigated whether keratinocytes possess autocrine and paracrine mechanisms for CC chemokine secretion and receptor expression as reported for the expression of interleukin 8 and its receptors. Reverse transcriptase polymerase chain reaction analysis demonstrated that CC chemokine receptor 3 mRNA is expressed constitutively in cultured keratinocytes. The signal quantities of the CC chemokine receptor 3 amplicons showed lower intensities for keratinocytes than for eosinophils. In situ hybridization techniques exhibited that basal cell layers of the epidermis were stained homogeneously for CC chemokine receptor 3 mRNA with a decreasing signal to the upper epidermis showing that differentiating and proliferating keratinocytes did express mRNA specific for CC chemokine receptor 3. Immunohistochemical studies confirmed low expression of CC chemokine receptor 3 protein on epidermal keratinocytes compared to the high level observed on infiltrating eosinophils. Furthermore, stimulation of cultured keratinocytes with eotaxin resulted in an increased [3H]thymidine incorporation indicating a role of CC chemokine receptor 3 in epidermal proliferation and differentiation. These data demonstrate that CC chemokine receptor 3 is expressed not only on hematopoietic cells but also on keratinocytes as nonhematopoietic cells with ectodermal origin. Therefore, the identification of CC chemokine receptor 3 on epidermal keratinocytes may indicate a role for CC chemokine receptor 3 and its ligands in skin physiology and pathophysiology.
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PMID:Characterization of the CC chemokine receptor 3 on human keratinocytes. 1128 22

Glucocorticoids are the most effective antiinflammatory drugs used in the treatment of asthma. They act by binding to a specific receptor (GR) that, upon activation, translocates to the nucleus and either increases (transactivates) or decreases (transrepresses) gene expression. Inhibition of pro-inflammatory transcription factors such as activator protein (AP)-1, signal transducers and activators of transcription (STATs), nuclear factor of activated T cells (NFAT) and nuclear factor (NF)-kappa B is thought to be a major action of glucocorticoids. Acetylation of histones allows unwinding of the local DNA structure and enables RNA polymerase II to enhance gene transcription. Histone acetylation is regulated by a balance between the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). GR acts as a direct inhibitor of NF-kappa B-induced HAT activity and also by recruiting HDAC2 to the NF-kappa B/HAT complex. A sub-group of patients with glucocorticoid-insensitive asthma have an inability to induce histone acetylation in response to dexamethasone suggesting reduced expression of a GR-specific HAT. This suggests that pharmacological manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases. Identification of the precise mechanism by which activated GR recruits HDAC2 may reveal new targets for the development of drugs that may dissociate the antiinflammatory actions of glucocorticoids from their side effects that are largely due to gene induction.
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PMID:Glucocorticoid-regulated transcription factors. 1144 48

Interleukin (IL)-9 is a T helper 2 cytokine implicated as a candidate gene and contributor to human asthma. We hypothesized that the inflammatory potential of bronchial epithelium is affected by its local environment and explored this hypothesis with respect to the effect of IL-9 on bronchial epithelium. We investigated the response of primary and immortalized human bronchial epithelial cells to IL-9 stimulation with respect to the release of T-cell chemoattractant factors. In response to IL-9, the HBE4-E6/E7 cell line, but not BEAS-2B cells, released the T-cell chemoattractants IL-16 and regulated on activation, normal T cells expressed and secreted (RANTES) in a dose-dependent fashion. We found a similar dose response to IL-9 in primary cells from bronchial brushings of healthy subjects and that nearly all of the T-cell chemoattraction was attributable to IL-16 and RANTES. Reverse transcriptase/polymerase chain reaction of BEAS-2B, HBE4-E6/E7, and primary cells from two subjects revealed messenger RNA for IL-9 receptor (IL-9R) alpha but not in BEAS-2B cells. Fluorescence-activated cell sorter analysis of HBE4-E6/E7 and primary cells confirmed surface expression of the IL-9 receptor. Costimulation of both cell types with IL-9 and antibody to either gamma-common chain or IL-9Ralpha completely blocked the release of T-cell chemoattractant activity, confirming the primary role of a functioning IL-9 receptor for IL-9 signaling in HBE4-E6/E7 and primary bronchial epithelial cells. We conclude that IL-9 is a stimulus for airway epithelial cell release of T-cell chemoattractant factors, which in turn may modulate the immune response in allergic airway inflammation.
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PMID:Il-9 stimulates release of chemotactic factors from human bronchial epithelial cells. 1158 13

Rhinoviruses, a genus of the family Picornaviridae, are the cause of more than 50% of respiratory tract infections. Complications of rhinovirus infections, which include otitis media, sinusitis, exacerbations of asthma, and other pulmonary diseases, can be significant in certain populations. Reverse transcriptase-polymerase chain reaction has allowed the identification of rhinoviruses and led to a greater appreciation of the role of this pathogen in upper and lower respiratory tract disease. Furthermore, antiviral agents with broad activity against rhinoviruses have recently been developed, have undergone clinical trials, but have not been approved for clinical use. By altering the clinical course of picornavirus infections, it may be possible to minimize their potential adverse consequences.
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PMID:Respiratory consequences of rhinovirus infection. 1257 7

The helper (Th)2 cell-attracting chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) are ligands for the chemokine receptor CCR4. A number of cellular sources of TARC and MDC have been identified, including not only macrophages, dendritic cells, and natural killer cells, but also bronchial epithelial cells. Recent studies report that TARC and MDC may serve as pivotal chemokines for the development of Th2-dominated experimental allergen-induced asthma. This study was designed to assess TARC and MDC production by CD4+ T cells, including naive T cells and memory/effector T cells, purified from peripheral blood mononuclear cells in patients with asthma. Asthmatic subjects included in this study had mild asthmatic symptoms, positive skin test responses to house dust mite allergen, and elevated level of Dermatophagoides farinae immunoglobulin E in the sera. CD4+ T cells--CD45RA+ CD4+ T cells--as naive T cells and CD45RO+ CD4+ T cells--as memory/effector T cells--were purified by negative selection from peripheral blood mononuclear cells obtained from asthmatic patients (n = 6) and healthy controls (n = 6). These cells and established Th1/Th2 cell lines were then cultured in the presence of both anti-CD3 and -CD28 antibodies. After 48 hr of incubation, concentrations of TARC, MDC, interleukin (IL)-4, IL-5, and interferon-gamma in the supernatants were measured by enzyme-linked immunoadsorbent assay. Reverse transcriptase-polymerase chain reaction was performed to analyze mRNA expression of TARC and MDC. Our results clearly showed that TARC and MDC were produced by activated CD45RA+ CD4+ T cells rather than by activated CD45RO+ CD4+ T cells, and the levels of these chemokines in the asthmatic patients were higher than those in the healthy controls. Furthermore, these chemokines production by Th2 cell lines were greater than those by Th1 cell lines, but the level were smaller than those by naive T cells. Our studies suggest that TARC and MDC are produced by naive T cells rather than by memory/effector T cells, including Th2 cells, in asthmatic patients, and these chemokines were produced at modest levels in any T-cell populations from healthy controls. Taken together, naive T cells in asthma have a peculiar function to produce TRAC and MDC, which contribute to local migration of Th2 cells into lung and lymphoid tissues, along with a function as precursor for memory/effector T cell. This novel function of naive T cells may be implicated in the development of asthma.
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PMID:Production of TARC and MDC by naive T cells in asthmatic patients. 1264 58

The aims of this study were to determine the cysteinyl leukotriene (CysLT) receptors expressed in the human saphenous vein, to examine contractile response to LTC4 and LTD4, to evaluate antagonist activity of montelukast, a specific CysLT1 receptor antagonist used in asthma, and to characterize the CysLT receptors involved in the contractile response. The analysis by reverse-transcriptase polymerase chain reaction indicated that CysLT1 and CysLT2 receptors are expressed by saphenous veins. In varicose vein rings, the potencies (pD2) of LTC4 and LTD4 were similar: 7.4 +/- 0.2 and 7.4 +/- 0.1, respectively. Pretreatment with acivicin, a gamma-glutamyl transpeptidase (gamma-GT) inhibitor, to prevent potential metabolism of LTC4 to LTD4, did not alter the response to LTC4. In nondistended vein rings from patients undergoing arterial bypass, the LTC4 pD2 was 7.8 +/- 0.1, and pretreatment with S-hexyl-GSH, a potent gamma-GT inhibitor, caused a fourfold rightward shift of the LTC4 concentration-response curve. In varicose and nondistended saphenous vein rings, montelukast (10(-8) and 10(-7) M) exerted a potent activity against LTD4 and LTC4, in the presence or absence of gamma-GT inhibitors. In varicose vein rings, the two active metabolites of montelukast also exerted antagonist activities with potencies similar to montelukast. BAY u9773 (CysLT2 agonist/dual CysLT1/CysLT2 antagonist) did not cause contraction and inhibited the LTC4- and LTD4-induced contractions. In conclusion, human saphenous veins express CysLT1 and CysLT2 receptors, but only CysLT1 receptors are implicated in the contraction.
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PMID:Characterization of cysteinyl leukotriene receptors on human saphenous veins: antagonist activity of montelukast and its metabolites. 1466 76

Hyaluronan (HA) is an important constituent of the extracellular matrix and accumulates during inflammatory lung diseases like asthma. Little is known about the factors that regulate HA synthesis by lung cells. Accordingly, we investigated the effect of T-helper 1 (TH1) and 2 (TH2) cytokines and the anti-inflammatory agents fluticasone and salmeterol on HA synthesis in human lung fibroblasts. Interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF)-alpha were the most potent stimulators of HA synthesis and when combined, caused synergistic increases in HA accumulation. Time-course analysis of HA accumulation and [3H]-glucosamine incorporation into HA demonstrated continued synthesis over the 24 h of stimulation. Peak synthesis at 6-12 h coincided with an increased proportion of high molecular weight HA. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that IL-1beta and TNF-alpha induced HA synthase-2 messenger RNA (mRNA) 3 h following stimulation and remained elevated throughout the 24-h stimulation period. Fluticasone inhibited IL-1beta and TNF-alpha induced HA synthesis (44.5%) whereas salmeterol had no effect. When combined, fluticasone and salmeterol inhibited HA synthesis to a greater extent (85.2%). Further, fluticasone attenuated IL-1beta and TNF-alpha stimulated hyaluronan synthase-2 messenger RNA (mRNA), and the addition of salmeterol cooperatively enhanced this inhibition. These results indicate that enhanced synthesis of HA by the proinflammatory cytokines IL-1beta and TNF-alpha can be abrogated by specific corticosteroid and beta2 blocker combinations shown to be effective in the treatment of asthma.
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PMID:Pro- and anti-inflammatory factors cooperate to control hyaluronan synthesis in lung fibroblasts. 1476 29


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