An important interplay exists between specific viral respiratory infections, atopy, and altered airway responsiveness in the development of asthma. The mechanistic basis of this interplay, however, remains to be identified. Based on our recent evidence that under certain pro-asthmatic conditions of airway smooth muscle (ASM) sensitization the ASM itself is induced to express proinflammatory cytokines that autologously elicit pro-asthmatic-like changes in its constrictor and relaxant responsiveness, the interrelated hypotheses are raised that: I: Specific viral respiratory pathogens modulate the acquisition and/or expression of altered ASM responsiveness in the atopic sensitized state; II: The virus-induced changes in ASM responsiveness are attributed to activation of specific intrinsic Fc receptor/cytokine-coupled autocrine interactions in the virus inoculated ASM; and III: The induced changes in responsiveness in virus-inoculated ASM are associated with perturbations in certain receptor/G protein-coupled transmembrane signaling mechanisms that regulate ASM contraction and relaxation. In addressing these hypotheses, experiments are proposed to examine mechanisms of altered agonist responsiveness in rabbit ASM tissues and cultured human ASM cells inoculated with either rhinovirus, respiratory syncytial virus, or parainfluenza virus in the absence and presence of passive atopic sensitization (AS) of the ASM with human atopic asthmatic serum or administered IgE immune complexes. A: To investigate mechanisms underlying virus-induced changes in ASM constrictor and relaxant responsiveness, we will examine: 1) the evoked release and autocrine actions of specific cytokines in virus-inoculated naive and AS-sensitized ASM; 2) the expression and activation of specific Fc receptors and cellular adhesion molecules (CAMs) and other co-stimulatory molecules in virus-inoculated ASM; and 3) whether virus-induced expression of cytokines and CAMs/co-stimulatory molecules in ASM elicits activation of naive T cells exposed to the virus-inoculated ASM. B: To investigate mechanisms of altered receptor/G protein-coupled transmembrane signaling in virus-inoculated ASM, we will examine whether induced changes in ASM responsiveness are attributed to: 1) altered constrictor agonist-mediated receptor/G protein-coupled accumulation, metabolism, and receptor binding of the key calcium-mobilizing second messenger, inositol 1,4,5-trisphosphate (Ins(I,,4,5)P3) in ASM; and 2) altered beta-adrenoceptor mediated modulation of constrictor agonist-induced accumulation, metabolism, and receptor binding of Ins(I,,4,5)P3. It is anticipated that the findings from these proposed studies would yield important new insights into the mechanistic interplay between viral respiratory pathogens, atopy, and altered airway responsiveness. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061038-08
Application #
7149160
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Noel, Patricia
Project Start
1999-04-01
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
8
Fiscal Year
2007
Total Cost
$362,680
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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