Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies in human asthmatics have suggested a defect in the beta-adrenergic pathway leading to cyclic adenosine monophosphate (cAMP) generation. Although these studies have suggested normal or increased numbers of beta-adrenergic receptors, limitations in the quantity of tissue available have not allowed further delineation of the biochemical or molecular mechanisms of human asthma. The basenji-greyhound (BG) dog model of nonspecific airway hyperreactivity displays similarities to human asthma, and altered functional response to beta-adrenergic agonists has been previously shown in airway tissue from this model. We have now correlated this functional impairment in beta-adrenergic response with a decreased generation of cAMP in response to isoproterenol. Organ bath studies and adenylyl cyclase assays of trachealis muscle revealed impaired responses to isoproterenol in the BG dog as compared with control dogs. Pretreatment of muscle strips from BG dogs with isoproterenol had no effect on subsequent dose-response curves to methacholine (pD2 = 7.17 +/- 0.13, 7.34 +/- 0.12, and 7.14 +/- 0.17 for control, 10(-6) M isoproterenol, and 10(-5) M isoproterenol, respectively), while muscle strips from mongrel dogs had a significant shift in methacholine responses after isoproterenol pretreatment (pD2 = 7.91 +/- 0.23, 7.48 +/- 0.29, and 6.98 +/- 0.33 for control, 10(-6) M isoproterenol, and 10(-5) M isoproterenol, respectively). Adenylyl cyclase activity in response to isoproterenol was 54% in the BG trachealis membranes as compared with mongrels. Functional and biochemical responses to forskolin, NaF, prostaglandin, and dibutyryl cAMP, and the quantity of G,alpha were similar in the BG and control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Jun
PMID:Impaired beta-adrenergic receptor activation of adenylyl cyclase in airway smooth muscle in the basenji-greyhound dog model of airway hyperresponsiveness. 839 28

We investigated the effects of Dermatophagoides farinae (Df) and interleukin (IL)-2 on the release of eosinophil colony-stimulating factor (Eo-CSF) activity from mononuclear cells (MNC) and lymphocytes of patients with bronchial asthma (BA) who were sensitive to Df to clarify its relationship with IL-5 and granulocyte/macrophage colony-stimulating factor (GM-CSF). MNC and T cells of patients cultured with IL-2 and Df released Eo-CSF activity. These Eo-CSF activities were partially inhibited by anti-IL-5 and anti-GM-CSF antibodies. In 11 of 15 cases studied, MNC from patients produced GM-CSF in response to IL-2. In four of 15 cases studied, MNC from patients produced GM-CSF in response to Df. On culture with IL-2 or Df, the releases of IL-5 into the medium by MNC from individual patients varied. The results indicate that in BA responsiveness of lymphocytes to Df is increased, and suggest that IL-5 and GM-CSF produced by T cells play a role in the induction of eosinophilia and the pathogenesis of BA.
Am J Respir Cell Mol Biol 1993 Oct
PMID:Production of interleukin-5 and granulocyte/macrophage colony-stimulating factor by T cells of patients with bronchial asthma in response to Dermatophagoides farinae and its relation to eosinophil colony-stimulating factor. 839 76

Tissue kallikrein is the major kininogenase detected in bronchoalveolar lavage fluids from asthmatics and may play a particularly important role in kinin generation during asthma. The present study was undertaken to determine the source of tissue kallikrein in the human lower airways. Specific antisera to human tissue kallikrein were used to localize this enzyme by immunocytochemistry in human trachea. Immunoreactive tissue kallikrein was localized in submucosal glands of the lamina propria but was not detected in epithelial cells or goblet cells. Specific staining for tissue kallikrein was not detected in all cells of the submucosal glands but was restricted to cells forming demilunes in the distal portions of the glands. When consecutive serial sections of submucosal glands were alternately stained using antiserum to tissue kallikrein and a periodic acid Schiff stain (to detect mucus), it was revealed that immunoreactive tissue kallikrein was present only in serous cells and not in mucus cells. The localization of tissue kallikrein to the serous cells of submucosal glands should facilitate studies to regulate the release of this enzyme. Regulation of tissue kallikrein release may provide a mechanism to reduce kinin generation during asthma.
Am J Respir Cell Mol Biol 1993 Jan
PMID:Localization of immunoreactive tissue kallikrein in human trachea. 841 52

Immunohistology and in situ hybridization were used to evaluate the presence, activation status, and cytokine mRNA profile of cells in the bronchial mucosa during human allergen-induced asthma. Fifteen atopic asthmatic subjects underwent inhalation challenge with allergen and with allergen diluent, performed in random order separated by an interval of at least 3 wk. Bronchial biopsies were obtained 24 h after challenge. Immunostaining revealed increases in the numbers of secreting eosinophils (EG2+; P < 0.05) and in interleukin-2 receptor (IL-2R)-positive cells (CD25+; P < 0.01) after allergen compared with diluent challenge. No differences were observed in the numbers of total leukocytes (CD45+), T lymphocytes (CD3+, CD4+, and CD8+), elastase-positive neutrophils, macrophages (CD68+), or mast cell subtypes (MCT+ or MCTC+). In situ hybridization revealed significant increases in the numbers of cells expressing mRNA for IL-5 (P < 0.02) and granulocyte/macrophage colony-stimulating factor (P < 0.01) after allergen compared with diluent challenge. A significant inverse relationship was observed between the number of cells expressing mRNA for IL-4 and for interferon-gamma (r = -0.75, P < 0.02). The results support the view that cytokines possibly from activated T lymphocytes may contribute to local eosinophil accumulation during allergen-induced asthma.
Am J Respir Cell Mol Biol 1993 Jan
PMID:Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics. 841 55

Recent in vitro studies have suggested that interleukin-4 (IL-4) may be involved in the preferential migration of eosinophils into the airways in allergic asthma through its capacity to selectively increase vascular cell adhesion molecule-1 (VCAM-1) expression on vessels. To test this hypothesis, we studied the expression of VCAM-1, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) on vascular endothelium in bronchial mucosal biopsies from 20 allergic asthmatics using an immunohistochemistry technique and related the observations to IL-4 levels in bronchoalveolar lavage (BAL) fluid simultaneously obtained and to eosinophil infiltration in the bronchial mucosa. IL-4 was detectable in BAL fluid from nine subjects (range, 15.1 to 110 pg/ml in 20-fold concentrated BAL fluid) (IL-4-positive asthmatics) but unmeasurable in the remaining 11 subjects (IL-4-negative asthmatics). The IL-4-positive asthmatics showed a significantly increased expression of VCAM-1 but not E-selectin and ICAM-1 on vessels as compared with both IL-4-negative asthmatics (P < 0.001) and diseased control subjects (P < 0.001). In asthmatics, VCAM-1 expression was positively correlated with BAL IL-4 levels (rs = 0.89; P < 0.0001). Moreover, there was a significant correlation between the endothelial expression of VCAM-1 and the number of eosinophils, but not neutrophils, in the bronchial submucosa (r2 = 0.76; P < 0.001). A significant correlation was also found between BAL IL-4 levels and the number of eosinophils. These results suggest that IL-4 is a VCAM-1-selective activator also in human airways and the VCAM-1-dependent pathways play a role in selective migration of eosinophils into the airways in allergic asthma, and support the hypothesis described above.
Am J Respir Cell Mol Biol 1996 Jan
PMID:Role of interleukin-4 and vascular cell adhesion molecule-1 in selective eosinophil migration into the airways in allergic asthma. 853 90

Atopic asthma is characterized by bronchial mucosal inflammation, involving eosinophils, mast cells, and lymphocytes. It has been suggested that the development and maintenance of this allergic inflammation is due to T-lymphocyte activation with predominant production of the cytokines interleukin 4 (IL-4) and IL-5. To address the ability of peripheral blood and bronchoalveolar lavage T-cells to generate IL-2, IL-4, or interferon gamma (IFN-gamma), we have employed a flow cytometric method which permits analysis of cytokine production at the single cell level within 5 h of obtaining cell samples. When stimulated with PMA and ionomycin, there was a greatly increased percentage of IFN-gamma-producing cells among bronchoalveolar lavage (BAL) T-cells from the subjects with asthma (median 74%), compared with atopic and nonatopic controls (35 and 43%, respectively; P>0.01). The proportion of BAL T-cells producing IL-4 was small (median 1.7%, range 0 to 7.8% in the asthmatic group). In all three groups, the proportion of BAL T-cells producing IL-2 or IFN-gamma was increased compared with T-cells from peripheral blood. There was no significant difference between the three groups in the percentage of BAL T-cells producing IL-2, or in the percentage of peripheral blood T-cells producing IFN-gamma, IL-2 or IL-4. These findings indicate that IL-4 production is confined to a relatively small proportion of airway and blood T-cells and that there is selective enhancement of IFN-gamma production by airway T-cells in asthma.
Am J Respir Cell Mol Biol 1996 Apr
PMID:T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma. 860 Sep 34

Lung transplant recipients can become asthmatic if they receive donor lungs from asthmatics. The maintenance of sensitivity in the lung allograft for inhaled allergens supports the concept that the mechanisms responsible for asthma are localized in the lungs, with a minimal systemic component. Pulmonary immunity to inhaled allergens is one mechanism which could be localized to the lung that would play a pivotal role in asthma. For example, the continued production of antibody to inhaled allergens in a human lung allograft could cause asthmatic responsiveness in the recipient. In this study, we tested the hypothesis that pulmonary immune cells continue to produce antibody in a canine allograft lung for relatively long times after transplantation. This was accomplished by immunizing four dogs by instillation of keyhole limpet hemocyanin (KLH) into a single lung lobe. After two challenges, the immunized lung from each dog was transplanted into a nonimmune recipient. Immune evaluations of recipients showed that anti-KLH antibody continued to be produced only in the donor lung for as long as 320 days after transplantation. Data from this study suggest that (1) immune cells in the lung can function independently from systemic immunity, (2) antibody production in the lung makes a significant contribution to blood antibody levels, and (3) immune cells in donor lungs can continue to produce antibody for relatively long times after transplantation. Therefore, immune cells in donor lungs from asthmatics could continue to produce antibody to allergens after transplantation, and this locally produced antibody may be responsible for the asthmatic responses observed in the recipients.
Am J Respir Cell Mol Biol 1996 Apr
PMID:Long-term antibody production in canine lung allografts: implications in pulmonary immunity and asthma. 860 Sep 38

A number of recent observations suggest a link between airway Cl-transport and asthma. We have previously described the properties of a voltage- and Ca2+ -dependent chloride channel present in airway epithelium. We now show that agents able to prevent indirectly induced bronchoconstriction (sodium cromoglycate, nedocromil sodium, and furosemide) reduce either the single-channel conductance or the open probability of this channel. The effects of these agents and the Ca2+ dependence of the channel are localized to the same surface, and we show that the channel possesses a specific divalent cation binding site, which responds to concentrations of Ca2+ found on the airway mucosal surface. No alteration of the single-channel properties of this channel were seen in cystic fibrosis epithelium. These data suggest a mechanism by which structurally diverse agents may influence asthma.
Am J Respir Cell Mol Biol 1996 Apr
PMID:Asthma prophylaxis agents alter the function of an airway epithelial chloride channel. 860 Sep 43

Glucocorticosteroids (GCS) are beneficial in allergic asthma. GCS therapy results in reduced mRNA expression of interleukin-4 (IL-4) and IL-5 in cells from bronchoalveolar lavage (BAL) but not of IFN-gamma. In vitro studies with blood-derived T cells, however, show inhibition of all three cytokines by GCS. We studied the effects of GCS on T cells from BAL in vitro, namely Th0-, Th1, and Th2-like clones; and we compared BAL- with blood-derived clones. Dexamethasone (DEX) inhibited the anti-CD3-induced production of IL-4, IL-5 and IFN-gamma in all 20 clones tested. IFN-gamma production was inhibited significantly less than IL-4 and IL-5. DEX enhanced the ratio IFN-gamma/IL-4 (mean +/- SEM: control, 28.7 +/- 17.6; with 10-7 M DEX, 55.0 +/- 27.5, P<0.005). Interestingly, two categories of clones were distinguished based on the effects of GCS on IL-2 production and IL-2R alpha expression and proliferation; 1) In low IL-2 producers DEX blocked IL-2 production and decreased IL-2R alpha expression and proliferation; 2) In high IL-2 producers DEX inhibited IL-2 production partially and enhanced IL-2R alpha expression and proliferation. Anti-IL-2 and anti-IL2R alpha blocked the DEX-induced increase in proliferation. High levels of added IL-2 induced the second type of response. In conclusion, the production of IL-4 and IL-5 by T-cell clones (derived either from BAL or blood) was more sensitive to inhibition by DEX than that of IFN-gamma, which may account for the therapeutic effects of glucocorticosteroids in patients with asthma. The differential effects of DEX on the proliferation of high and low IL-2 producers in vitro may implicate a selective outgrowth of Th1-like T cells in vivo in patients treated with steroids.
Am J Respir Cell Mol Biol 1996 Apr
PMID:Glucocorticosteroids affect functions of airway- and blood-derived human T-cell clones, favoring the Th1 profile through two mechanisms. 860 Sep 44

A murine model of allergen-induced airway inflammation and epithelial phenotypic change, and the time-courses of these events, are described. Mice were sensitized to ovalbumin using an adjuvant-free protocol, and challenged by multiple intratracheal instillations of ovalbumin by a non-surgical technique. Many of the characteristic features of human atopic asthma were seen in the mice. A marked eosinophilic infiltration of lung tissue and airways followed allergen challenge, and its severity increased with each challenge, as did the number of eosinophils in the blood. Lymphocytes, neutrophils, and monocytes also invaded the lungs. Airway macrophages showed signs of activation, their appearance resembling those recovered from antigen-challenged human asthmatic airways. The airway epithelium was thickened and displayed a marked goblet cell hyperplasia in terminal bronchioles and larger airways. After repeated challenges, the reticular layer beneath the basement membrane of the airway epithelium showed fibrosis, reproducing a commonly observed histologic feature of human asthma. Goblet cell hyperplasia began to appear before eosinophils or lymphocytes had migrated across the airway epithelium, and persisted for at least 11 days after the third intratracheal challenge with ovalbumin, despite the number of inflammatory cells in the lungs and airways having decreased to near-normal levels by 4 days. Plugs of mucus occluded some of the airways. These results indicate that some of the phenotypic changes in airway epithelium that follow an allergic response in the lung can be initiated before the migration of eosinophils or lymphocytes across the epithelial layer.
Am J Respir Cell Mol Biol 1996 May
PMID:Lung inflammation and epithelial changes in a murine model of atopic asthma. 862 47


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