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)

Eosinophil recruitment to airway tissue is a key feature of asthma, and release of a wide variety of toxic mediators from eosinophils leads to the tissue damage that is a hallmark of asthma pathology. Factors that control the release of these toxic mediators are targets for potential therapeutic intervention. Protease-activated receptors (PARs) are a novel class of receptors that are activated by cleavage of the N terminus of the receptor by proteases such as thrombin or trypsin-like enzymes. To date, PAR1-4 have been identified, and there are several studies that have demonstrated the expression of PARs in airway tissue, particularly the respiratory epithelium. We have investigated whether eosinophils express PARs and if activation of these receptors will then trigger a functional response. Using a combination of reverse transcriptase-polymerase chain reaction, Western blotting, and flow cytometry analysis, we have demonstrated that eosinophils express PAR1 and PAR2. FACS analysis showed that PAR1 could be clearly detected on the surface of the cells, whereas PAR2 appeared to be primarily intracellular. Trypsin and the PAR2 agonist peptide were seen in trigger shape change, release of cysteinyl leukotrienes, and most obviously, generation of reactive oxygen species. In contrast, thrombin had no effect on eosinophil function. The PAR1 agonist peptide did have a minor effect on eosinophil function, but this was most likely down to its ability to activate PAR1 and PAR2. These results demonstrate that PAR2 is the major PAR receptor that is capable of modulating eosinophil function.
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PMID:Expression of and functional responses to protease-activated receptors on human eosinophils. 1283 43

Extracellular matrix (ECM) expansion contributes to airway remodeling in asthma. This study examines the effect of leukotriene D4 (LTD4), combined with epidermal growth factor (EGF), on proteoglycan synthesis by cultured human bronchial smooth muscle cells (BSMCs). LTD4 plus EGF stimulated proliferation of BSMCs with increased versican synthesis. Further, versican mRNA splice variants, V0 and V1, were differently regulated in BSMCs by LTD4 plus EGF. Synthesis of [35S]-methionine labeled versican V0, as a percentage of total versican, was doubled. This upregulation was confirmed by Western analysis. Synthetic changes were paralleled by alterations in versican V0 mRNA. The effects of LTD4 and EGF on proteoglycan synthesis were inhibited by montelukast. Similar upregulation of versican V0 was observed in arterial smooth muscle cells (ASMCs) stimulated with LTD4 plus EGF as measured by western and reverse transcriptase-polymerase chain reaction analyses. Changes in ECM in the asthmatic airway may parallel those in atherosclerotic lesions where proliferating ASMCs synthesize a versican-rich expanded ECM. Inhibition of these processes could lead to reduced tissue expansion in the early phases of asthma progression.
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PMID:Regulation of proteoglycan synthesis by leukotriene d4 and epidermal growth factor in bronchial smooth muscle cells. 1285 4

Leukotriene (LT)C4, a potent chemical mediator in bronchial asthma, is metabolised to the less active LTE4 via LTD4 in two consecutive reactions catalysed by enzymes of the glutamyl transpeptidase and dipeptidase families. The activities of these catabolic enzymes may be influenced by glucocorticosteroids. This study was conducted to examine whether this inactivation of LTC4 is affected by dexamethasone (DEX) in transformed human bronchial epithelial cells and normal human bronchial epithelial cells. After incubation with DEX for 0-5 days, cells were resuspended in the presence of exogenous LTC4, and conversion of LTC4 to LTE4 was measured using high-performance liquid chromatography. Gamma-glutamyl transpeptidase (GGT) and GGT-related enzyme (GGTRE) messenger ribonucleic acid (mRNA) expression were examined using reverse transcriptase-polymerase chain reaction analysis, and GGT activity by enzyme assay. Conversion to LTE4 was accelerated by DEX pretreatment. GGTRE but not GGT mRNA expression was enhanced after incubation with DEX. The results indicate that dexamethasone transcriptionally upregulates the activity of gamma-glutamyl transpeptidase-related enzyme in human bronchial epithelial cells, which accelerates inactivation of leukotriene C4 via conversion to leukotriene E4. This is a novel mechanism of glucocorticosteroids in human bronchial epithelial cells.
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PMID:Dexamethasone accelerates catabolism of leukotriene C4 in bronchial epithelial cells. 1288 48

Vascular endothelial growth factor (VEGF) is highly expressed in the airway of patients with asthma. Whether VEGF affects eosinophil function in vitro and if VEGF receptors are involved was tested. Eosinophils were from venous blood of healthy donors. Cell migration was studied by micropore filter assays. Signaling mechanisms required for VEGF-dependent migration were tested using signaling enzyme blockers. Expression of flt-1 and KDR/flk-1 mRNA in eosinophils was demonstrated in reverse transcriptase-polymerase chain reaction, and receptor expression was investigated by fluorescence-activated cell sorting analysis. Eosinophil cationic protein release was measured in eosinophil supernatants by enzyme-linked immunosorbent assay. VEGF significantly stimulated eosinophil chemotaxis via activation of protein kinase C and phosphatidylinositol 3'-kinase. The effect on migration was reversed by an antibody against VEGF receptor flt-1, but not by an antibody against KDR/flk-1. Expression of VEGF receptor flt-1 mRNA was shown and synthesis of VEGF receptor in eosinophils is suggested by detection of VEGF receptor immunoreactivity on the cell surface. Data suggest that VEGF receptor flt-1 is expressed by eosinophils whose activation with VEGF stimulates directed migration and release of eosinophil cationic protein. Thus, VEGF may play an important role in the modulation of eosinophilic inflammation.
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PMID:Expression and function of the vascular endothelial growth factor receptor FLT-1 in human eosinophils. 1460 15

In the airways, increases in cholinergic nerve activity and cholinergic hypersensitivity are associated with chronic obstructive pulmonary disease and asthma. However, the contribution of individual muscarinic acetylcholine receptor subtypes to the constriction of smaller intrapulmonary airways that are primarily responsible for airway resistance has not been analyzed. To address this issue, we used videomicroscopy and digital imaging of precision-cut lung slices derived from wild-type mice and mice deficient in either the M1 (mAChR1-/- mice), M2 (mAChR2-/- mice), or M3 receptor subtype (mAChR3-/- mice) or lacking both the M2 and M3 receptor subtypes (mAChR2/3-/- double-knockout mice). In peripheral airways from wild-type mice (mAChR+/+ mice), muscarine induced a triphasic concentration-dependent response, characterized by an initial constriction, a transient relaxation, and a sustained constriction. The bronchoconstriction was diminished by up to 60% in mAChR3-/- lungs and was completely abolished in mAChR2/3-/- lungs. The sustained bronchoconstriction was reduced in mAChR2-/- bronchi, and, interestingly, the transient relaxation was absent; the bronchoconstriction in response to 10-8 M muscarine was increased by 158% in mAChR1-/- mice. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed that the disruption of specific mAChR genes had no significant effect on the expression levels of the remaining mAChR subtypes. These results demonstrate that cholinergic constriction of murine peripheral airways is mediated by the concerted action of the M2 and M3 receptor subtypes and suggest the existence of pulmonary M1 receptor activation, which counteracts cholinergic bronchoconstriction. Given the important role of muscarinic cholinergic mechanisms in pulmonary disease, these findings should be of considerable therapeutic relevance.
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PMID:Role of muscarinic receptor subtypes in the constriction of peripheral airways: studies on receptor-deficient mice. 1464 75

Mast cells constitute a significant proportion of cells infiltrating nasal polyp tissue, and epithelial cells may release stem cell factor (SCF), a cytokine with chemotactic and survival activity for mast cells. We aimed to assess the expression of SCF in human nasal polyp epithelial cells (NPECs) as related to patients' clinical phenotypes. Nasal polyp tissues were obtained from 29 patients [including nine with aspirin (ASA)-hypersensitivity and 12 with bronchial asthma] undergoing polypectomy for nasal obstruction. Epithelial cells were obtained following 6-week culture of nasal polyps explants. The SCF released into the culture supernatant was assessed by enzyme-linked immunosorbent assay (ELISA) and total SCF mRNA in the polyp tissue was determined by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). For the whole group of patients, the number of polypectomies correlated with expression of SCF mRNA (r = 0.62; P < 0.005), SCF protein in the NPECs supernatants (r = 0.39; P < 0.05) and with density of mast cells in epithelial layer (r = 0.37; P < 0.05) and stromal layer (r = 0.5; P < 0.01) of nasal polyps. The SCF/beta-actin mRNA ratios were significantly higher in ASA-hypersensitive (AH) asthmatics (median 0.97, range: 0.8-1.5) when compared with ASA-tolerant (AT) patients (median 0.5, range: 0.1-0.7; P < 0.001). The SCF protein concentration in NPEC supernatants was also significantly higher in AH asthmatics (median 1.10 pg/microg DNA, range: 0.4-1.9) when compared with AT patients (median 0.1 pg/microg DNA, range: 0.02-1.2; P < 0.001). In the subpopulation of ASA-sensitive asthmatics the number of polypectomies correlated also with the density of mast cells and eosinophils in the polyp tissue.
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PMID:Association of stem cell factor expression in nasal polyp epithelial cells with aspirin sensitivity and asthma. 1581 8

Human metapneumovirus is a paramyxovirus that was discovered in 2001 in the Netherlands. Epidemiologic studies have shown it to be a major cause of acute respiratory tract disease in normal infants and children worldwide, with a seasonal occurrence and spectrum of clinical illness most similar to the closely related respiratory syncytial virus. The greatest prevalence of severe disease requiring hospitalization in otherwise healthy children appears to be in those aged between 6 and 12 months, older than the peak age of hospitalizations for respiratory syncytial virus. Human metapneumovirus is also a significant cause of acute respiratory disease in adults, particularly the elderly and those with comorbid conditions such as chronic obstructive pulmonary disease, asthma, and cancer. Because there is no rapid diagnostic assay, reverse transcriptase polymerase chain reaction is most widely used. Animal models have been developed, and candidate live-attenuated vaccines are in preclinical trials, offering the potential for future interventions in high-risk groups.
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PMID:Human Metapneumovirus: An Important Cause of Respiratory Disease in Children and Adults. 1584 23

Bronchial asthma is defined as a chronic airway inflammatory disease characterized by sustained activation of many inflammatory cells including mast cells. Urocortin (UCN) is synthesized and secreted by human mast cells and activated mast cells release more UCN. On the other hand, UCN can induce mast cell degranulation and generation of many proinflammatory factors. The purpose of this study was to examine the expression profile of UCN in rat lung with allergic asthma. Twenty-four male Sprague-Dawley rats were allocated to normal control, asthma model, and dexamethasone group, respectively. Animals were actively sensitized by subcutaneous injection of ovalbumin (OVA) and challenged by an aerosol of 1% OVA 2 weeks after sensitization. Both UCN mRNA and peptide were expressed in normal rat lungs. Rats in asthma model group developed severe infiltration of inflammatory cells and inflammation in airway, together with a significantly up-regulated expression of urocortin mRNA detected by semi-quantitative reverse transcriptase-polymerase chain reaction and peptide measured both by immunohistochemistry and Western blot analysis. In contrast, treatment with dexamethasone resulted in markedly ameliorated airway inflammation and alleviated airway inflammatory cell infiltration, coupled with a significantly decreased urocortin expression. Regression analysis revealed a positive correlation between urocortin expression and the number of inflammatory cells in bronchoalveolar lavage fluid (P<0.01). In the present study, we first demonstrated that UCN was locally produced in rat lungs and expressed more pronouncedly in inflammatory airway of asthmatic rats. Glucocorticoid treatment markedly reduced the production of UCN in asthmatic lung tissues. Peripherally produced UCN in lung may act as a possible local autocrine and paracrine immune-inflammatory mediator in inflammatory airway of allergic asthma rats.
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PMID:Enhanced expression of urocortin in lung tissues of rats with allergic asthma. 1642 7

Human rhinoviruses (HRV), members of the Picornaviridae family, are comprised of over 100 different virus serotypes. HRV represent the single most important etiological agents of the common cold [Arruda, E., Pitkaranta, A., Witek Jr., T.J., Doyle, C.A., Hayden, F.G., 1997. Frequency and natural history of rhinovirus infections in adults during autumn. J. Clin. Microbiol. 35, 2864-2868; Couch, R.B., 1990. Rhinoviruses. In: Fields, B.N., Knipe, D.M. (Eds.), Virology. Raven Press, New York, pp. 607-629; Turner, R.B., 2001. The treatment of rhinovirus infections: progress and potential. Antivir. Res. 49 (1), 1-14]. Although HRV-induced upper respiratory illness is often mild and self-limiting, the socioeconomic impact caused by missed school or work is enormous and the degree of inappropriate antibiotic use is significant. It has been estimated that upper respiratory disease accounts for at least 25 million absences from work and 23 million absences of school annually in the United States [Anzueto, A., Niederman, M.S., 2003. Diagnosis and treatment of rhinovirus respiratory infections. Chest 123 (5), 1664-1672; Rotbart, H.A., 2002. Treatment of picornavirus infections. Antivir. Res. 53, 83-98]. Increasing evidences also describe the link between HRV infection and more serious medical complications. HRV-induced colds are the important predisposing factors to acute otitis media, sinusitis, and are the major factors in the induction of exacerbations of asthma in adults and children. HRV infections are also associated with lower respiratory tract syndromes in individuals with cystic fibrosis, bronchitis, and other underlying respiratory disorders [Anzueto, A., Niederman, M.S., 2003. Diagnosis and treatment of rhinovirus respiratory infections. Chest 123 (5), 1664-1672; Gern, J.E., Busse, W.W., 1999. Association of rhinovirus infections with asthma. Clin. Microbiol. Rev. 12 (1), 9-18; Pitkaranta, A., Arruda, E., Malmberg, H., Hayden, F.G., 1997. Detection of rhinovirus in sinus brushings of patients with acute community-acquired sinusitis by reverse transcription-PCR. J. Clin. Microbiol. 35, 1791-1793; Pitkaranta, A., Virolainen, A., Jero, J., Arruda, E., Hayden, F.G., 1998. Detection of rhinovirus, respiratory syncytial virus, and coronavirus infections in acute otitis media by reverse transcriptase polymerase chain reaction. Pediatrics 102, 291-295; Rotbart, H.A., 2002. Treatment of picornavirus infections. Antivir. Res. 53, 83-98]. To date, no effective antiviral therapies have been approved for either the prevention or treatment of diseases caused by HRV infection. Thus, there still exists a significant unmet medical need to find agents that can shorten the duration of HRV-induced illness, lessen the severity of symptoms, minimize secondary bacterial infections and exacerbations of underlying disease and reduce virus transmission. Although effective over-the-counter products have been described that alleviate symptoms associated with the common cold [Anzueto, A., Niederman, M.S., 2003. Diagnosis and treatment of rhinovirus respiratory infections. Chest 123 (5), 1664-1672; Gwaltney, J.M., 2002a. Viral respiratory infection therapy: historical perspectives and current trials. Am. J. Med. 22 (112 Suppl. 6A), 33S-41S; Turner, R.B., 2001. The treatment of rhinovirus infections: progress and potential. Antivir. Res. 49 (1), 1-14; Sperber, S.J., Hayden, F.G., 1988. Chemotherapy of rhinovirus colds. Antimicrob. Agents Chemother. 32, 409-419], this review will primarily focus on the discovery and development of those agents that directly or indirectly impact virus replication specifically highlighting new advances and/or specific challenges with their development.
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PMID:Rhinovirus chemotherapy. 1667 37

Human metapneumovirus (hMPV) is a recently isolated virus, mostly associated with acute lower respiratory infection in children, of which symptoms are similar to those of respiratory syncytial virus (RSV) infection. The aim of our study was to determine the frequency of hMPV in hospitalized children with acute respiratory tract disease in Korea. Nasal aspirates from hospitalized children with respiratory infections under 15 yr old between December 2003 and February 2005 were included in the study. Each sample was analyzed for RSV, adenovirus, influenza virus A and B, and parainfluenza virus by indirect fluorescent assay (IFA). F-gene sequences were used for PCR for the detection and sequencing of hMPV. In total 381 samples, negative samples in which any viral pathogen could not be identified by IFA were 231 cases. hMPV was detected using reverse transcriptase-PCR (RT-PCR) in 28 of 231 (12.1%) children who were not infected with another respiratory viruses. The hMPV-infected children were diagnosed as having pneumonia, bronchiolitis, bronchial asthma exacerbation, croup, and upper respiratory tract infection. Most of the RT-PCR positive samples for hMPV were collected in winter season. These results suggest that hMPV may be a responsible pathogen causing acute respiratory tract infection in Korean children.
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PMID:Human metapneumovirus infection in hospitalized children with acute respiratory disease in Korea. 1704 16


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