Atopy and airway exposure to aeroallergens and microbial pathogens are primary risk factors for development of asthma. Compelling evidence that airway smooth muscle (ASM) plays a critical role in regulating the airway asthmatic phenotype includes that demonstrating that ASM expresses receptors for atopic and non-atopic stimuli that represent the above risk factors, and responds to these sensitizing stimuli by releasing cytokines, notably including Th2-type cytokines, that evoke pro-asthmatic changes in ASM constrictor and relaxation responsiveness. Recent studies demonstrate that activation of CD4+ T cells by superantigen (SAg)-presenting ASM cells also elicits Th2 cytokine release coupled to changes in ASM responsiveness. Contrasting these pro- asthmatic actions, our new findings demonstrate that ASM also exhibits a Th2 cytokine-induced mechanism that enables it to activate endogenous glucocorticoids (GCs) and, thereby, homeostatically oppose the adverse effects of Th2 cytokine signaling on ASM function. This new evidence, together with that demonstrating that both the cytokine-induced pro-asthmatic and homeostatic GC signaling in sensitized ASM are attributed to activation of MAPK signaling, raise the hypotheses that: I: The pro-asthmatic changes in ASM function elicited by atopic and non-atopic sensitizing stimuli, and by ASM/T cell interaction, are mediated by MAPK-dependent regulation of both cytokine expression and action;II: GC-mediated protection of ASM from the pro-asthmatic effects of cytokines is due to MAPK-dependent upregulation of GC signaling in the sensitized state;and III: ASM isolated from asthmatic patients exhibits enhanced MAPK-regulated pro-asthmatic signaling and impaired MAPK-regulated CG signaling. These hypotheses will be addressed in studies on ASM cells isolated from non- asthmatic and asthmatic airways. Accordingly, I: To investigate MAPK-dependent induction of pro-asthmatic changes in responsiveness in sensitized ASM, we will examine: 1) MAPK-dependent regulation of cytokine release and action in ASM sensitized by atopic (IgE) and by non-atopic stimuli including rhinovirus, dust mite allergen, or lipopolysaccharide;2) Gi protein-mediated MAPK activation, resulting in altered PDE4 expression and its regulation of ASM contraction and relaxation;3) MAPK-dependent regulation of CD4+ T cell activation by SAg-presenting ASM cells. II. To investigate MAPK-dependent regulation of GC signaling, we will examine MAPK-dependent regulation of the GC-activating enzyme, 11ss-hydroxysteroid dehydrogenase-1 (11ss-HSD1), and glucocorticoid receptor (GR) signaling in sensitized ASM;III. To determine whether asthmatic ASM exhibits perturbations in MAPK-dependent regulation of pro-asthmatic and GC signaling, we will compare asthmatic vs. non-asthmatic sensitized ASM cells with respect to differences in regulation of PDE4 expression and action, GC activation and signaling, and T cell activation by SAg-presenting ASM cells. The results from these studies are anticipated to identify key intrinsic perturbations in the signaling mechanisms in ASM that underlie expression of the airway asthmatic phenotype.

Public Health Relevance

Atopy, allergen exposure, and viral respiratory infections are key risk factors for the development of asthma. By comparing how non-asthmatic and asthmatic airway smooth muscle respond to stimulation by these risk factors, this project will importantly contribute to an improved understanding of the mechanisms that underlie the development of asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097739-04
Application #
8322627
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Program Officer
Banks-Schlegel, Susan P
Project Start
2009-08-01
Project End
2013-08-31
Budget Start
2012-08-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$407,138
Indirect Cost
$159,638
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
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