Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Because adenosine narrows asthmatic airways, is released during hypoxia and by mast cells, and is antagonized by theophylline, it may play a role in asthma. I characterized the first step in pulmonary responses to adenosine: its adenosine receptor. Plasma membranes, prepared from macroscopically normal human peripheral lung, were incubated with 10 nM 5'-N-ethylcarboxamido[3H]adenosine ([3H]NECA) and various concentrations of competing ligand under experimentally determined optimal conditions: 4 degrees C, pH 7.4, 5 mM MgCl2, 1.8 mg protein/ml, 30-min incubation time. Bound and free ligand were separated by rapid vacuum filtration, and the radioactive counts were analyzed using a weighted, non-linear, least-squares curve-fitting program, LIGAND. Analyzed together, the data from the lungs of 6 patients revealed a single binding site with a dissociation constant (Kd) for NECA of 200 nM +/- 14% and a receptor concentration of 543 fmol/mg protein +/- 13%. Analyzed separately, the individual Kds ranged from 133 to 430 nM and the receptor concentrations from 338 to 811 fmol/mg protein. Adenosine receptor ligands competed with NECA in an A2 rank order of potency: NECA greater than 8-phenyltheophylline greater than 3-isobutyl-1-methylxanthine greater than theophylline greater than N6-L-phenylisopropyladenosine greater than N6-D-phenylisopropyladenosine greater than N6-cyclohexyladenosine. Theophylline bound to the receptor with an inhibition constant (Ki = 70.9 microM +/- 28%) near the therapeutic range (28 to 56 microM). Cromolyn also bound with high affinity (Ki = 5.42 microM +/- 47%). I conclude that human lung adenosine receptors: (1) are single-site receptors, probably of the A2 subtype and (2) bind to both theophylline and cromolyn.
Am J Respir Cell Mol Biol 1990 Feb
PMID:Characterization of the human peripheral lung adenosine receptor. 240 76

Endothelin, synthesized by endothelial cells, is the most potent vasoconstrictor and bronchoconstrictor agent known. We investigated endothelin release from human bronchial epithelial cells and the binding of the peptide to autologous bronchial smooth muscle cells in culture. Epithelial and smooth muscle cells were isolated by enzymatic digestion of bronchial tissue obtained on surgery, and cultured to confluency by standard methods. Epithelial cells stained positively for cytokeratin filaments. Smooth muscle cells stained uniformly for alpha-smooth muscle actin. Immunoreactive endothelin contents in the supernatants of epithelial cells extracted on C8 Amprep columns were evaluated by radioimmunoassay. Epithelial cells released appreciable amounts of immunoreactive endothelin into the culture medium (from 0.65 to 2.1 pmol/ml). A single specific binding site for [125I]endothelin 1 was identified on bronchial smooth muscle cells with an apparent Kd of 113 pM and a maximal binding capacity of 22.1 fmol/10(6) cells. At room temperature the binding was saturable, reached equilibrium at 120 min (25 pM endothelin 1), and was slowly and incompletely reversed by unlabeled endothelin over a period of 8 h. Conditioned medium from epithelial cells inhibited the [125I]endothelin 1 binding, dose dependently, and the effect was antagonized by monospecific antiserum. Thus, human bronchial smooth muscle cells possess specific binding sites for endothelin 1 and human bronchial epithelial cells secrete an endothelin-like material. This may have a role in the pathogenesis of asthma.
Am J Respir Cell Mol Biol 1990 Aug
PMID:Specific binding of endothelin on human bronchial smooth muscle cells in culture and secretion of endothelin-like material from bronchial epithelial cells. 219 95

A thickened bronchial epithelial basement membrane has long been regarded as a histopathologic characteristic of bronchial asthma. As we had previously demonstrated that this phenomenon is due to the deposition of interstitial collagens and fibronectin, we have now sought to determine the nature of the cell responsible for this process by studying endobronchial biopsies from eight normal and seven asthmatic volunteers by immunohistochemistry and electron microscopy. Biopsies were stained with PR 2D3, a monoclonal antibody to myofibroblasts of the pericrypt sheath of the colon and a monoclonal antibody to alpha-smooth muscle actin. The thickness of the subepithelial collagen and the organelle content of the cells therein were determined by electron microscopy. The subepithelial collagen thickness in the normal subjects ranged from 2.16 to 6.26 microns, while that in the asthmatic subjects ranged from 3.75 to 11.1 microns (Mann-Whitney test; P = 0.05). Elongated cells in the collagen layer were identified by staining with PR 2D3. As this antibody also stains smooth muscle, consecutive frozen sections were stained for alpha-smooth muscle actin and the number of positive cells per millimeter of basement membrane was subtracted from the count for PR 2D3. This yielded a count of 4.9 to 9.4 cells/mm in the normal subjects and 11.9 to 20.6 cells/mm in the asthmatics (P = 0.001). There was a highly significant correlation between the depth of subepithelial collagen and the number of PR 2D3-positive, alpha-smooth muscle actin-positive cells (Spearman rank correlation; r = 0.764 and P = 0.006). Electron microscopy confirmed the myofibroblastic nature of these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1990 Nov
PMID:Myofibroblasts and subepithelial fibrosis in bronchial asthma. 222 5

Epithelial shedding is a characteristic feature of asthmatic airways and has been attributed to eosinophil products. We have examined the interaction of purified intraperitoneal guinea pig eosinophils with or without platelet-activating factor (PAF, 10(-7) M) or lyso-PAF (10(-7) M) with guinea pig tracheal epithelium in vitro. At 0, 4, 14, and 24 h, the percentage of ciliation of the tracheal circumference (CTC) was measured by light microscopy and the ciliary beat frequency (CBF) by photometry. PAF-activated eosinophils (50 x 10(6) cells/ml) disrupted the epithelium, mean CBF and CTC being reduced by 77.8 +/- 5.8% (mean +/- SEM; P less than 0.001 versus control) and 94.2 +/- 1.4% (P less than 0.001) over 24 h, respectively. PAF (10(-7) M) alone had no significant effect. Lyso-PAF with eosinophils (50 x 10(6) cells/ml) also reduced mean CBF and CTC but to a lesser extent. Eosinophils alone also led to a reduction of 36.2 +/- 11.4% in mean CBF and 53.0 +/- 15.5% in CTC, but these changes were not significant. The PAF antagonist, WEB 2086 (10(-6) M), significantly inhibited the mean CBF and CTC reduction due to PAF-activated eosinophils by 61.5 +/- 17.2% (P less than 0.01) and 20.8 +/- 6.5% (P less than 0.05), respectively. In addition, catalase (1,125 U/ml) partially inhibited the mean CBF and CTC reduction induced by PAF-activated eosinophils. Intraperitoneal neutrophils (PMN) (50 x 10(6) cells/ml) also disrupted epithelium but to a lesser extent (24-h reduction: 34.2 +/- 12.7% for mean CBF and 60.2 +/- 13.2% for CTC, respectively). Stimulation with PAF (10(-7) M) had no further effect. Marked exfoliation of the epithelial layer was observed after 14 h of incubation with activated eosinophils. We concluded the PAF-activated eosinophils are capable of grossly disrupting ciliated epithelium and may contribute to epithelial damage observed in asthma.
Am J Respir Cell Mol Biol 1990 Apr
PMID:The effects of activated eosinophils and neutrophils on guinea pig airway epithelium in vitro. 232 67

Recently our laboratory has shown that neutrophils contain enzymatic activity within their lysosomal granules which will generate chemotactic activity for neutrophils and tumor cells from the fifth component of complement (C5). We have now expanded this initial observation and have demonstrated that eosinophils can release enzymatic activity from their lysosomal granules upon stimulation with immune complexes or opsoninized zymosan, but not with C5a or synthetic chemotactic peptides. Furthermore, the enzymatic activity released from the eosinophil lysosomal granules can cleave C5 into eosinophil-specific chemotactic activity. The generation of the eosinophil chemotactic activities from C5 is blocked by prior treatment of the eosinophil preparations with a number of protease inhibitors. The eosinophil-derived C5 cleaving activity possesses a pH optimum of 7.2, thus suggesting the enzymatic activity is a neutral protease. The demonstration that enzyme activities derived from eosinophils have the ability to generate eosinophil chemotactic factor(s) from C5 may explain why eosinophils are the predominant inflammatory cell in both nasal polyps and in the nasopharynx and bronchi of patients with allergic conditions such as hay fever and asthma.
Virchows Arch B Cell Pathol Incl Mol Pathol 1981
PMID:Digestion of the fifth component of complement by eosinophil lysosomal enzymes. Production of eosinophil specific chemotactic activity. 611 42

Epithelial damage in the airways is a feature often observed in patients with asthma and is probably caused by the interaction of epithelial cells with leukocytes. As adhesion molecules are thought to be important in this interaction, we analyzed the expression and modulation of adhesion molecules on primary cultured human bronchial epithelial cells and the bronchial epithelial cell lines BEAS-2B and NCI-H292. E-selectin, P-selectin, and VCAM-1 were absent under basal and stimulated conditions. The adhesion molecules ICAM-1 (CD54), LFA-3 (CD58), and CD44 (H-CAM) were expressed basally on primary cultured human bronchial epithelial cells and the BEAS-2B and NCI-H292 cell lines. CD44 and LFA-3 expression did not change after stimulation with IFN-gamma or TNF-alpha. In contrast, ICAM-1 expression on human bronchial epithelial cells and BEAS-2B cells could be increased by incubation with PMA, IFN-gamma, TNF-alpha, and especially with the combination of IFN-gamma and TNF-alpha. The maximal ICAM-1 expression on both epithelial cell types was obtained with the combination of TNF-alpha and IFN-gamma after 48 h of incubation. The NCI-H292 cell line was different in that it only showed increased ICAM-1 expression after stimulation with PMA and IFN-gamma and not by the combination of IFN-gamma and TNF-alpha or with TNF-alpha alone. In conclusion, the bronchial epithelial cells tested express several adhesion molecules, but only ICAM-1 expression was influenced by inflammatory cytokines.
Am J Respir Cell Mol Biol 1993 Dec
PMID:Expression and modulation of adhesion molecules on human bronchial epithelial cells. 750 27

Endothelin exists as three isoforms (ET-1, ET-2, and ET-3) and exhibits vasoconstricting, bronchoconstricting, and growth-promoting properties in vascular smooth muscle. In the airways, ET-1 immunoreactivity and mRNA have been detected and localized to the epithelium, smooth muscle, and endothelium in different species, including humans. It has been suggested that ET-1 may have a role in the airway smooth muscle hyperplasia and hypertrophy seen in patients with bronchial asthma. We studied ovine airway smooth muscle cells (SMC) in vitro and showed saturable binding of [125I]ET-1 with a dissociation constant (Kd) of 0.4 nM and high affinity binding sites (Bmax) for ET-1 (104 fmol/10(6) cells). This binding was functional as ET-1 promoted mitogenesis of these muscle cells as measured by increased cell number in the absence of serum. Twenty-four hours after exposing the cells to graded doses of ET-1 from 1 pM to 1 microM, cell number increased significantly over control in a dose-dependent manner. ET-1 also enhanced the transient expression of c-fos mRNA by 2.5-fold over control, with maximal expression occurring at 30 min. These observations provide evidence that: (1) airway SMC possess high affinity binding sites for ET-1, and (2) ET-1 is mitogenic for airway SMC as determined by increased cell number and amplification of c-fos mRNA expression. ET-1 may have a fundamental role in influencing the growth of smooth muscle in the airways.
Am J Respir Cell Mol Biol 1994 Mar
PMID:Endothelin-1 promotes mitogenesis in airway smooth muscle cells. 750 12

Interleukin (IL)-6 is a pleiotropic cytokine produced by a wide variety of cells including fibroblasts, macrophages, endothelial cells, and T and B lymphocytes. Regulated IL-6 production is an important part of normal biologic homeostasis, and abnormal IL-6 production has been associated with a large number of diseases including asthma and lung allograft rejection. Glucocorticoids are potent anti-inflammatory agents that are widely used to suppress pulmonary inflammation. To further understand the mechanisms underlying this inhibition, we determined whether glucocorticoid compounds regulate human lung fibroblast IL-6 production and characterized the mechanisms of the effects that were noted. These studies demonstrate that glucocorticoids inhibit IL-1-induced IL-6 production in a dose-dependent fashion. A greater than 95% decrease in IL-6 production was seen with 10(-6) and 10(-7) M dexamethasone, prednisolone, and hydrocortisone, and IC50 values for these agents were approximately 5 x 10(-10), 5 x 10(-9), and 10(-8) M, respectively. mRNA analysis demonstrated that these alterations in protein production were associated with proportionate decreases in IL-6 mRNA accumulation, and that this suppression of IL-6 mRNA could be reversed by the glucocorticoid receptor antagonist RU 486. Nuclear run-on studies demonstrated that glucocorticoids inhibit-IL-1-induced IL-6 gene transcription. However, the magnitude of this effect could not fully account for the potency of the glucocorticoid-induced alterations in IL-6 mRNA accumulation and protein production since 10(-6) M dexamethasone caused only a 50% decrease in IL-1-induced IL-6 gene transcription.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 Jun
PMID:Glucocorticoid inhibition of interleukin-1-induced interleukin-6 production by human lung fibroblasts: evidence for transcriptional and post-transcriptional regulatory mechanisms. 751 73

An important locus for Atopy (familial asthma, hay fever and eczema) has been localized to the 11q12-q13 region with the minimum recombination fraction around the CD20 gene. We have constructed a 2.8 megabase (Mb) Yeast Artificial Chromosome (YAC) contig of the candidate region using 15 STSs. A total of seven genes have been mapped within this interval in the order cen-OSBP-TCN1-GIF-Fc epsilon RI beta-CD20-CD5-PGA-q(ter) and can be covered by a minimum of eight YAC clones. Contig integrity was assayed with fluorescence in-situ hybridization (FISH) and the mapping of YAC ends on somatic cell and radiation hybrid panels. A long range restriction map of the contig has been constructed to establish the order of and distance between loci. Two promising candidates for the atopy locus, the beta subunit of the high affinity immunoglobulin E receptor (Fc epsilon RI beta) and CD20, a molecule involved in B cell differentiation, have been placed within the contig.
Hum Mol Genet 1994 May
PMID:A 2.8 Mb YAC contig in 11q12-q13 localizes candidate genes for atopy: Fc epsilon RI beta and CD20. 752 9

Eosinophils play a critical role in the pathogenesis of bronchial asthma by releasing various mediators. To understand the mechanisms of eosinophil migration to the site of inflammation, we examined the expression of adhesion molecules in the bronchial tissues of asthmatic subjects with air flow limitation. By immunohistochemical analysis, Mac-1, LFA-1, and VLA-4 were strongly positive in eosinophils and mononuclear cells infiltrated in the bronchial mucosa and submucosa. Their number was significantly increased compared with those in control tissue. Immunolocalization for ICAM-1, the ligand of Mac-1 and LFA-1, was detected in the endothelial cells of capillaries and venules, in the mononuclear cells in submucosa, and in the basal layer of the epithelium. Endothelial cells in capillaries and venules were also strongly positive for VCAM-1, the ligand of VLA-4. Immunolocalization for E-selectin was detected in some endothelial cells in capillaries and venules in bronchial submucosa, whereas there were very few positive cells in the bronchial tissues from control subjects. In situ hybridization demonstrated ICAM-1 mRNA expression in the endothelial cells and mononuclear cells in bronchial submucosa. Immunoelectron microscopy for ICAM-1, VCAM-1, and E-selectin demonstrated de novo synthesis of these molecules and their expression along the luminal cell membrane of endothelial cells. These results suggested that ICAM-1, VCAM-1, and E-selectin were newly synthesized prior to spontaneous asthma attacks, and that their expression, particularly that of VCAM-1, may play a key role in eosinophil infiltration into the airway.
Am J Respir Cell Mol Biol 1995 Jan
PMID:In situ expression of the cell adhesion molecules in bronchial tissues from asthmatics with air flow limitation: in vivo evidence of VCAM-1/VLA-4 interaction in selective eosinophil infiltration. 752 29


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