Although the molecular mechanisms that result in the development of asthma are yet to be fully understood, it is generally accepted that inflammatory processes contribute importantly to sustaining the disease. Up-regulation of immunoglobulin E (IgE) has also been incriminated as a contributing factor in part because of the association between high IgE) has also been incriminated as a contributing factor in part because of the association between high IgE levels and asthma. However, athe precise mechanisms by which IgE may contribute to asthmatic inflammation remain to be defined. Over the last eight years, our laboratory has worked extensively on the structure and function of the high-affinity IgE receptor (FcepsilonRI). In this process, we have produced a number of unique reagents such as cDNAs and genes encoding the alpha, beta and gamma subunits of the tetrameric FcepsilonRI (alphabetagamma2), multiple antibodies against the subunits of human Fcepsilom RI and a panel of useful transfectants. We therefore are now in a unique position to apply our basic knowledge about Fcepsilon RI to the analysis of the allergic inflammation in asthma. New studies from this laboratory are particularly relevant in to this question. We have demonstrated not only that blood monocytes express (FcepsilonRI, but also that the level of receptor expression is substantially up-regulated on monocytes of atopic when compared to normal subjects. In addition, mononuclear phagocytes, including alveolar macrophages, have been shown to be an important cell type in the airways and have the capacity to produce a wide variety of inflammatory mediators. Based on these findings, we propose to test the hypothesis that FcepsilonRI is also up-regulated on monocytes and alveolar macrophages of asthmatics and that this upregulation represents an important mechanistic link between IgE and allergic inflammation. In this scenario, FcepsilonRI allows alveolar macrophages to be stimulated through IgE and antigen, which leads to the production of various inflammatory mediators responsible, at least in part, for the asthmatic inflammation. To test this hypothesis, we will; 1) compare the Fcepsilon RI expression levels on blood monocytes and alveolar macrophages in four categories of subjects (atopic asthmatic, atopic non-asthmatic, non-atopic asthmatic, and normal), and investigate whether IgE is bound in vivo to this receptor, 2) analyze in these four groups of subjects the structure of monocyte- expressed FcepsilonRI and its capacity to transduce intracellular signals and to generate inflammatory mediators such as LTB4, TNF-alpha and MIP- 1alpha; 3) analyze the mechanisms responsible for FcepsilonRI up- regulation.
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| Moore, Paul E; Calder, Mark M; Silverman, Eric S et al. (2003) Effect of dexamethasone on beta2-adrenergic desensitization in airway smooth muscle: role of the ARG19 polymorphism. Chest 123:368S-9S |
| Storm van's Gravesande, Karin; Wechsler, Michael E; Grasemann, Hartmut et al. (2003) Association of a missense mutation in the NOS3 gene with exhaled nitric oxide levels. Am J Respir Crit Care Med 168:228-31 |
| Shore, Stephanie A; Moore, Paul E (2003) Regulation of beta-adrenergic responses in airway smooth muscle. Respir Physiol Neurobiol 137:179-95 |
| Levy, Bruce D; De Sanctis, George T; Devchand, Pallavi R et al. (2003) Lipoxins and aspirin-triggered lipoxins in airway responses. Adv Exp Med Biol 525:19-23 |
| Shore, Stephanie A; Moore, Paul E (2002) Effects of cytokines on contractile and dilator responses of airway smooth muscle. Clin Exp Pharmacol Physiol 29:859-66 |
| Silverman, Edwin K; Mosley, Jonathan D; Palmer, Lyle J et al. (2002) Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes. Hum Mol Genet 11:623-32 |
| Lahiri, Thomas; Moore, Paul E; Baraldo, Simonetta et al. (2002) Effect of IL-1beta on CRE-dependent gene expression in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 283:L1239-46 |
| Silverman, Edwin K; Palmer, Lyle J; Mosley, Jonathan D et al. (2002) Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease. Am J Hum Genet 70:1229-39 |
| Levy, B D; Serhan, C N (2002) Polyisoprenyl phosphates: natural antiinflammatory lipid signals. Cell Mol Life Sci 59:729-41 |
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