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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histamine is a major mediator of the mast cells that are present between epithelial cells in asthma. In asthma, there is an increased expression of ICAM-1 and HLA-DR and an increased spontaneous release of fibronectin. The effect of histamine was tested on bronchial epithelial cells obtained by bronchial brushing from 22 nonasthmatic subjects. The activation of epithelial cells was assessed by immunocytochemical analysis of the expression of membrane markers (ICAM-1 and HLA-DR) using the alkaline phosphatase-anti-alkaline phosphatase method and the release of fibronectin (enzyme immunoassay). Time-response (three experiments) and dose-response (six experiments) curves showed that the maximal effect was obtained after an incubation time of 24 h and a dose of 1 microM of histamine. For this time course and concentration, there was a highly significant increase in the number of cells expressing ICAM-1 (before histamine: 10 +/- 11%; after histamine: 32 +/- 20%; P < 0.001) and HLA-DR (before histamine: 8 +/- 7%; after histamine: 23 +/- 20%; P < 0.001) and in the release of fibronectin (before histamine: 30 +/- 20 ng/10(5) viable cells; after histamine: 61 +/- 35 ng/10(5) viable cells; P < 0.003). Cycloheximide blocked these effects, suggesting that histamine requires protein synthesis for its action. Pyrilamine (H1-blocker) and ranitidine (H2-blocker) at a concentration of 10 microM decreased the effect of histamine. However, there was no additive effect when both antagonists were added. This study suggests that mast cells present in the airways have a role in the activation of epithelial cells.
Am J Respir Cell Mol Biol 1993 Oct
PMID:Activation by histamine of bronchial epithelial cells from nonasthmatic subjects. 810 36

The expression of the monocyte chemoattractant protein (MCP-1), a member of the chemokine family of low molecular weight cytokines, was assessed by immunohistochemistry in bronchial biopsies from 12 asthmatic and 12 normal subjects. Both a monoclonal antibody (F9) and a polyclonal antibody were employed to detect MCP-1, while the mouse myeloma protein (MOPC21) was used as a negative control. Strong positive reactions for MCP-1 were seen in the bronchial epithelium. Subepithelial macrophages, blood vessels, and bronchial smooth muscle were also stained. Hue-saturation-intensity color image analysis was used to quantify reactions of the monoclonal antibody in the epithelial and subepithelial layers. With the monoclonal antibody, asthmatic biopsies showed 51.8 +/- 3.7% (mean +/- SEM) of the epithelium staining positively, whereas normal subjects reacted much less, with 6.4 +/- 1.9% of the epithelium staining (P < 0.0001); there was no overlap between the two groups. Likewise, staining was increased in the subepithelium of asthmatic airway biopsies, with 11.5 +/- 3.1% and 2.0 +/- 1.0% staining positively in asthmatic and normal subepithelium, respectively, (P < 0.002). There was a significant correlation between staining of the epithelium and subepithelium (r = 0.77, P < 0.001). The polyclonal anti-MCP-1 antibody also gave strong reactions in the epithelium and subepithelium, with 34.0 +/- 7.8% of the asthmatic and 1.6 +/- 1.0% of the normal bronchial epithelium staining positively (P < 0.0001). These increased levels of MCP-1 in the asthmatic airways suggest that they may play a role in macrophage recruitment and activation and thereby contribute to the inflammatory pathology of bronchial asthma.
Am J Respir Cell Mol Biol 1994 Feb
PMID:Increased expression of the monocyte chemoattractant protein-1 in bronchial tissue from asthmatic subjects. 811 Apr 69

Asthma is characterized by the presence of an inflammatory cell infiltrate in the bronchial mucosa consisting of activated mast cells, eosinophils, and T cells. Several cytokines are considered to play a pivotal role in this response, particularly interleukin (IL)-4, IL-5, IL-6, and tumor necrosis factor-alpha (TNF-alpha). In this study, we have used immunohistochemistry applied to thin glycol methacrylate sections of bronchial mucosal biopsies to define the cellular provenance of these cytokines in normal and asthmatic airways. Both the asthmatic and normal mucosa contained numerous cells staining positively for all four cytokines, with the majority identified as mast cells by their tryptase content. Eosinophils also accounted for some IL-5 immunostaining in the asthmatic biopsies. By using two monoclonal antibodies directed to different epitopes of IL-4, we provide tentative evidence for enhanced IL-4 secretion in asthma. Similarly, a sevenfold increase in the number of mast cells staining for TNF-alpha in the asthmatic biopsies suggests that this cytokine is also up-regulated in this disease. These findings clearly identify human mast cells as a source of IL-4, IL-5, IL-6, and TNF-alpha and add to the view that, along with T cells, mast cells may play an important role in initiating and maintaining the inflammatory response in asthma.
Am J Respir Cell Mol Biol 1994 May
PMID:Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. 817 9

The establishment of animal models of asthma is critical to elucidate the mechanisms involved in the pathogenesis of the disease. In the present study, we have used a parasite antigen from Schistosoma mansoni eggs, which induces a TH2 response, to elicit a pulmonary inflammatory reaction that resolves after 3 to 4 days. Histologic examination of the lungs of soluble egg antigens (SEA) or saline vehicle-challenged mice demonstrated a large influx of cells in the antigen- but not vehicle-challenged mice, thus demonstrating an antigen-specific reaction. A characteristic influx of eosinophils could be detected as early as 8 h, with significant increases at 24 to 72 h after challenge. An assessment of the bronchial alveolar lavage (BAL) fluid demonstrated dominant neutrophil infiltration at 8 h, with a subsequent decrease to background by 48 h. In addition, peak monocyte infiltration occurred at 24 h, and peak eosinophil extravasation into the airway was shown at 48 h. The examination of leukocyte infiltrates in the interstitium in dispersed lung preparations again demonstrated early neutrophil and monocyte infiltration at 8 h after challenge, with increases in lymphocyte and eosinophil infiltrates at 24 h. Examination of interleukin-4 (IL-4) production in the BAL fluid demonstrated the presence of IL-4 early in the response, with levels peaking between 8 and 24 h after antigen challenge, with no detectable IL-4 in the saline vehicle-challenged mice. Mice treated with anti-IL-4 antibodies demonstrated a tenfold decrease in BAL eosinophil influx at 48 h after challenge and a reduction in total pulmonary leukocyte cellularity.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 May
PMID:Interleukin-4-dependent pulmonary eosinophil infiltration in a murine model of asthma. 817 15

Substance P has several inflammatory effects on the airways mediated via neurokinin 1 receptors (NK1Rs) and, if released from sensory nerves, may amplify the chronic inflammation seen in asthma. Northern blot analysis of NK1R mRNA in lung showed a 52 +/- 10% (S.E.M.; P < 0.01) increase in mRNA in the asthmatic lung compared with non-asthmatic control tissue. NK1R mRNA was reduced by 84.5 +/- 1.9% after incubation with dexamethasone (1 microM) for 3 h (P < 0.01). In contrast, NK2R mRNA was unaltered in asthmatic lungs and dexamethasone treatment had no effect on the level of NK2R mRNA. These results suggest that chronic inflammation in asthma may result in increased NK1R gene expression and that this effect is reversed by glucocorticosteroids.
J Mol Endocrinol 1993 Aug
PMID:Increased tachykinin receptor gene expression in asthmatic lung and its modulation by steroids. 824 Jun 67

Theophylline, as used for the treatment of asthma and chronic obstructive pulmonary disease, may have several effects, including direct bronchodilation, improvement in diaphragmatic and ciliary function, and possibly immune modulation. In this study, we quantified the capacity for theophylline to inhibit natural killer (NK) cells and investigated the mechanism(s) that mediate this inhibition. Theophylline at 10 micrograms/ml and 20 micrograms/ml inhibited the tumoricidal activity of isolated peripheral blood lymphocytes (PBL) by 19 +/- 5% and 36 +/- 6%, respectively (n = 6). Using fluorescence-activated cell sorting, we purified NK cells from PBL and tested theophylline's effects on the kinetics of tumor lysis (Vmax) and on tumor binding. Theophylline at 20 micrograms/ml reduced Vmax by 40 +/- 9% but had no effect on tumor binding. We compared the effects of theophylline, which is both a phosphodiesterase (PDE) inhibitor and an adenosine receptor (AdR) antagonist, with agents that range from relatively pure AdR antagonists to pure PDE inhibitors. Inhibition of NK activity occurred only with PDE inhibitors. We also extracted lymphocyte PDE and observed a direct correlation (r2 = 0.99) between theophylline's activity as a PDE inhibitor and its capacity to inhibit NK activity. These results suggest that theophylline inhibits NK cytotoxicity through its activity as a PDE inhibitor. The clinical relevance of these findings awaits further study.
Am J Respir Cell Mol Biol 1993 Dec
PMID:Inhibition of natural killer cell activity by therapeutic levels of theophylline. 825 97

Stimulated migration of eosinophils out of the bloodstream and into the lung is key in the development of tissue eosinophilia and inflammation in asthma. Platelet-activating factor (PAF) has been implicated as an important inflammatory mediator in asthma pathogenesis in part because of its chemotactic capacity. We therefore studied the ability of PAF to induce human peripheral blood eosinophil migration through naked filters and human umbilical vein endothelial cells (HUVECs) cultured on these filters. PAF induced eosinophil migration through both barriers in a time-dependent fashion, with maximal eosinophil migration occurring at 180 min. Significant eosinophil migration was observed at PAF concentration > or = 0.1 microM and was dose dependent up to 10.0 microM. No significant differences in eosinophil chemotactic responses were noted between naked filter and HUVEC barriers. The PAF receptor antagonist, WEB 2086, inhibited (> 85%) eosinophil transendothelial migration when co-incubated with PAF or when used as a pretreatment of either the eosinophils or HUVECs. However, WEB 2086 pretreatment of HUVECs did not inhibit PAF-induced neutrophil transendothelial migration, nor did it affect leukotriene B4-induced neutrophil or eosinophil transendothelial migration. Thus, the data indicate that the endothelial cell plays an important role in PAF-induced eosinophil inflammatory processes. Moreover, these data suggest that PAF's pathogenic role in asthma may in part be due to its ability to stimulate eosinophil migration across endothelial barriers and into the airways.
Am J Respir Cell Mol Biol 1993 Jan
PMID:Platelet-activating factor-induced human eosinophil transendothelial migration: evidence for a dynamic role of the endothelium. 838 Feb 50

The challenge of previously sensitized guinea pigs with aerosolized ovalbumin resulted in impairment of the beta-adrenoceptor-mediated relaxation as measured by the in vitro isometric assay of tracheas preconstricted with endothelin-1 or carbamylcholine. Numbers and affinities of beta-adrenoceptors in lung membranes of these animals were not altered under these conditions, although the antigen challenge caused an inflammatory response, as evident from the accumulation of inflammatory cells in the bronchoalveolar lavage fluids. In order to investigate the pathophysiologic role of inflammation in hyperreactive airways, isolated guinea pig tracheas were cultured with proinflammatory cytokines such as human recombinant tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), or interleukin-2 (IL-2). None of these cytokines affected the contractile response of tracheas to carbamylcholine. After preconstriction with carbamylcholine, the TNF-alpha- and IL-1 beta-pretreated tissues produced a significant reduction in the maximal relaxation induced by isoproterenol, whereas the IL-2 pretreatment had no effect. The reduction of the isoproterenol-mediated relaxation by the IL-1 beta treatment was time and dose dependent. Our present observations suggest that in vitro incubation of naive tracheas with proinflammatory cytokines is able to reproduce apparent beta-adrenoceptor impairment as seen in the airways of antigen-challenged guinea pigs of asthma model.
Am J Respir Cell Mol Biol 1993 Feb
PMID:Organ culture with proinflammatory cytokines reproduces impairment of the beta-adrenoceptor-mediated relaxation in tracheas of a guinea pig antigen model. 838 Dec 92

It has long been hypothesized that a defective beta 2-adrenergic receptor (beta 2AR) may be a pathogenic factor in bronchial asthma. We examined the gene encoding the beta 2AR to assess the frequency of polymorphisms in 51 patients with moderate to severe asthma and 56 normal subjects. Nine different point mutations were found in both heterozygous and homozygous forms at nucleic acid residues 46, 79, 100, 252, 491, 523, 1053, 1098, and 1239. No mutations resulting in large deletions or frame shifts were detected. Of these nine polymorphisms, four were found to cause changes in the encoded amino acids at residues 16, 27, 34, and 164. The most frequent polymorphisms were arginine 16 to glycine (Arg16-->Gly) and glutamine 27 to glutamic acid (Gln27-->Glu). The other two polymorphisms, valine 34 to methionine, and threonine 164 to isoleucine, occurred in only four subjects. The incidence of beta 2AR homozygous polymorphisms was no greater in asthmatic patients as compared with controls (Arg16-->Gly: 53% versus 59%, Gln27-->Glu: 24% versus 29%, respectively; P = NS). Some subjects were found to have both of these polymorphisms simultaneously, but there was no difference in incidence between the two groups, with 23% of asthmatics and 28% of normal subjects being homozygous for both polymorphisms. The apparently normal subjects with both polymorphisms did not have subclinical hyperreactive airways disease as determined by methacholine challenge testing. In the asthma group, one mutation (Arg16-->Gly) identified a subset of patients with a distinct clinical profile.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Mar
PMID:Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. 838 11

It is well known that antigen challenge of sensitized subjects can induce an immediate and late asthmatic response, airway eosinophilia, and hyperreactivity. Using our modified guinea pig asthma model, we investigated the superoxide anion generation from eosinophils and macrophages recovered from bronchoalveolar lavage (BAL) 24 h after antigen (ovalbumin) challenge. We also investigated the effect of formoterol, a new long-acting selective beta 2-agonist, on these functions. Antigen challenge increased the total cell counts and the ratio of eosinophils in BAL. Eosinophils and macrophages were collected using discontinuous density centrifugation. Antigen challenge enhanced superoxide anion generation from eosinophils, from 5.39 +/- 1.08 to 13.19 +/- 1.95 nmol 60 min after phorbol myristate acetate (PMA) (1 ng/ml) activation, and 0.22 +/- 0.49 to 3.34 +/- 1.67 nmol 40 min after platelet-activating factor (PAF) (10(-6) M) activation. Formoterol treatment before antigen challenge prevented these enhancements. Superoxide anion generation from macrophages was also enhanced by antigen challenge, from 6.57 +/- 0.76 to 10.66 +/- 0.88 nmol 60 min after PMA activation, and 4.20 +/- 1.17 to 6.63 +/- 0.64 nmol 60 min after PAF activation. Formoterol, however, failed to inhibit enhancement of superoxide anion generation from macrophages. These results show antigen challenge of sensitized guinea pigs induces an increase of eosinophils and macrophages in BAL and enhances the functional characteristics of both cells. Formoterol had inhibitory effects on the enhancement of superoxide anion generation from eosinophils but did not have this effect on macrophages.
Am J Respir Cell Mol Biol 1993 May
PMID:Effect of formoterol on superoxide anion generation from bronchoalveolar lavage cells after antigen challenge in guinea pigs. 838 28


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