An important interplay exists between viral respiratory infections, atopy, and altered airway responsiveness in the development of asthma. The mechanistic basis of this interplay, however, remains to be identified. In view of the latter, and given our recent evidence demonstrating that an autocrine system involving Fc receptor/cytokine interactions in airway smooth muscle (ASM) autologously induces its altered responsiveness in the atopic asthmatic state, secondary to perturbed receptor/G protein-coupled transmembrane signaling, the following interrelated hypotheses are raised: I: That specific viral respiratory pathogens modulate the acquisition of altered ASM responsiveness in the atopic asthmatic sensitized state; II: That this action of viral pathogens on ASM responsiveness is related to altered receptor/G protein-coupled transmembrane signaling in sensitized ASM; and III: That the viral-mediated changes in transmembrane signaling in ASM are attributed to induced altered autocrine interactions between specific Fc receptors, proinflammatory cytokines, and adhesion molecules in atopic sensitized ASM. In addressing these hypotheses, studies will examine mechanisms of altered ASM responsiveness in isolated rabbit and human ASM tissue and cultured ASM cells passively sensitized with human atopic/asthmatic serum in the absence and presence of inoculation with rhinovirus, parainfluenza type 3, or respiratory syncytial virus. I.A: To investigate mechanisms underlying viral pathogen-induced perturbations in ASM constrictor responsiveness, we will examine changes in: 1) the expression and modulatory actions of specific G proteins; and 2) agonist/receptor-coupled accumulation of the key Ca2+-mobilizing second messenger, inositol 1,4,5 trisphosphate (Ins(1,4,5)P3) its metabolism, and its intracellular receptor binding. I.B: To investigate mechanisms underlying viral pathogen-induced perturbations in beta-adrenoceptor-mediated ASM relaxation, we will examine changes in: 1) specific G protein expression and regulation of beta-adrenergic receptor binding and transduction; and 2) beta-adrenoceptor/G protein-coupled modulation of constrictor agonist-induced accumulation of Ins(1,4,5)P3, its metabolism, and its receptor binding. Finally, II: To assess the autocrine role of Fc receptor/cytokine interactions in mediating virus-induced changes in ASM responsiveness in the atopic sensitized state, we will examine: 1) whether the above viral pathogens induce altered autologous expression and autocrine actions of specific cytokines in sensitized ASM; and 2) whether the altered release of these cytokines is coupled to changes in expression of specific Fc receptors and adhesion molecules in sensitized ASM. Collectively, the proposed studies should yield important new insights into the potential autocrine role of the ASM in the mechanistic interplay between viral respiratory pathogens, atopy, and altered ASM responsiveness in the atopic/asthmatic sensitized state.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL061038-01A1
Application #
2851828
Study Section
Special Emphasis Panel (ZRG1-RAP (01))
Project Start
1999-04-01
Project End
2003-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hu, Aihua; Josephson, Maureen B; Diener, Barry L et al. (2013) Pro-asthmatic cytokines regulate unliganded and ligand-dependent glucocorticoid receptor signaling in airway smooth muscle. PLoS One 8:e60452
Josephson, Maureen B; Jiao, Junfang; Xu, Shuyun et al. (2012) IL-13-induced changes in endogenous glucocorticoid metabolism in the lung regulate the proasthmatic response. Am J Physiol Lung Cell Mol Physiol 303:L382-90
Nino, Gustavo; Hu, Aihua; Grunstein, Judith S et al. (2012) G Protein ??-subunit signaling mediates airway hyperresponsiveness and inflammation in allergic asthma. PLoS One 7:e32078
Nino, Gustavo; Grunstein, Michael M (2010) Current concepts on the use of glucocorticosteroids and beta-2-adrenoreceptor agonists to treat childhood asthma. Curr Opin Pediatr 22:290-5
Nino, Gustavo; Hu, Aihua; Grunstein, Judith S et al. (2010) Mechanism of glucocorticoid protection of airway smooth muscle from proasthmatic effects of long-acting beta2-adrenoceptor agonist exposure. J Allergy Clin Immunol 125:1020-7
Hu, Aihua; Fatma, Sumbul; Cao, Jing et al. (2009) Th2 cytokine-induced upregulation of 11beta-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function. Am J Physiol Lung Cell Mol Physiol 296:L790-803
Nino, Gustavo; Hu, Aihua; Grunstein, Judith S et al. (2009) Mechanism regulating proasthmatic effects of prolonged homologous beta2-adrenergic receptor desensitization in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 297:L746-57
Hu, Aihua; Nino, Gustavo; Grunstein, Judith S et al. (2008) Prolonged heterologous beta2-adrenoceptor desensitization promotes proasthmatic airway smooth muscle function via PKA/ERK1/2-mediated phosphodiesterase-4 induction. Am J Physiol Lung Cell Mol Physiol 294:L1055-67
Veler, Haviva; Hu, Aihua; Fatma, Sumbul et al. (2007) Superantigen presentation by airway smooth muscle to CD4+ T lymphocytes elicits reciprocal proasthmatic changes in airway function. J Immunol 178:3627-36
Shan, Xiaoyin; Hu, Aihua; Veler, Haviva et al. (2006) Regulation of Toll-like receptor 4-induced proasthmatic changes in airway smooth muscle function by opposing actions of ERK1/2 and p38 MAPK signaling. Am J Physiol Lung Cell Mol Physiol 291:L324-33

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