Studies are proposed to determine the mechanisms by which immune activation and adhesion of eosinophils are translated into augmented bronchomotor tone as occurs in human asthma. Through a collaboration established by the Lung Institute of NHLBI and the Research ministry of the Republic of Germany, a method has been developed to assess the effects of activated human eosinophils on microsections of explanted human bronchial airways. These studies utilize using a newly developed technique for videomicrometry and on-line computerized integration of airway lumenal diameter in 250 microl microwell chambers. A central hypothesis of these investigations is that adhesion to endothelium and/or cellular matrix primes eosinophils for release of inflammatory mediators that cause augmented airway smooth muscle contraction. In an initial series of experiments, studies will be performed to assess the mechanism by which prolonged exposure of eosinophils (greater than or equal to 24 h) to myeloma protein IgE and/or interleukin (IL)-4 causes upregulation of the native secretory response to stimulation by antigenic cross linking using a novel anti-IgE antibody (TN142). These studies examine the hypothesis that immune stimulation per se is an initial priming event in the activation of eosinophils during endothelial transmigration. In a second series of studies, the augmenting effect of inflammatory cell binding to endothelium on the bronchoconstriction caused by immune- and pharmacologically activated eosinophils will be examined. Preliminary studies indicate that ligation to human umbilical cord vein endothelial cells (HUVEC) causes upregulated secretion of eosinophils and augmented narrowing of human bronchial explants. Further studies will examine the specific ligands responsible for this augmented narrowing and a mechanism for selective blockade of this response. In a third series of studies, the effect of eosinophil binding to the matrix protein, fibronectin, through the surface ligand VLA-4 also will be examined. Preliminary investigations indicate that this is an extremely slow binding process that confers sustained augmentation of eosinophil secretory activity. Studies are proposed to examine directly the effects of this prolonged binding on the contractile response elicited by immunologically activated eosinophils on human bronchial explants and to determine the mechanism of this augmented contraction through selective blockage with monoclonal antibodies to specific cell surface ligands, e.g., anti-VLA-4 (HP 2/1). In each investigation, the role of the low affinity CD23 receptor, FcepsilonRII, in activating eosinophil secretion and consequent airway contractility will be examined, and the relationship between the upregulation of this receptor caused by exposure to rhIL-4 and IgE will be assessed. Comparable studies will be done using pharmacological activation with exogenous platelet activating factor, and the potential role for direct immune regulation of bronchial contraction through the low affinity eosinophil IgE receptor will be examined. All essential methodologies for proposed studies have been developed in preliminary studies for this proposal. Data derived from these studies should elucidate mechanisms by which an unusual (eosinophilic) mode of inflammation confers hyperresponsiveness upon human bronchial airways as occurs in human asthma.
| Chen, Bohao; Moore, Tamson V; Li, Zhenping et al. (2014) Gata5 deficiency causes airway constrictor hyperresponsiveness in mice. Am J Respir Cell Mol Biol 50:787-95 |
| Ma, Lan; Brown, Melanie; Kogut, Paul et al. (2011) Akt activation induces hypertrophy without contractile phenotypic maturation in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 300:L701-9 |
| Motika, Caroline A; Papachristou, Charalampos; Abney, Mark et al. (2011) Rising prevalence of asthma is sex-specific in a US farming population. J Allergy Clin Immunol 128:774-9 |
| McConville, John F; Fernandes, Darren J; Churchill, Jason et al. (2011) Nuclear import of serum response factor in airway smooth muscle. Am J Respir Cell Mol Biol 45:453-8 |
| Chen, Bohao; Yates, Elena; Huang, Yong et al. (2009) Alternative promoter and GATA5 transcripts in mouse. Am J Physiol Gastrointest Liver Physiol 297:G1214-22 |
| Ober, Carole; Nord, Alex S; Thompson, Emma E et al. (2009) Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J Lipid Res 50:798-806 |
| Bellenguez, Céline; Ober, Carole; Bourgain, Catherine (2009) A multiple splitting approach to linkage analysis in large pedigrees identifies a linkage to asthma on chromosome 12. Genet Epidemiol 33:207-16 |
| Bellenguez, Celine; Ober, Carole; Bourgain, Catherine (2009) Linkage analysis with dense SNP maps in isolated populations. Hum Hered 68:87-97 |
| Pinto, Jayant M; Hayes, M Geoffrey; Schneider, Daniel et al. (2008) A genomewide screen for chronic rhinosinusitis genes identifies a locus on chromosome 7q. Laryngoscope 118:2067-72 |
| Hershenson, Marc B; Brown, Melanie; Camoretti-Mercado, Blanca et al. (2008) Airway smooth muscle in asthma. Annu Rev Pathol 3:523-55 |
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