Although ozone (O3) induces asthma exacerbations, methacholine airway hyperresponsiveness (AHR) and neutrophilic airway inflammation associated with increases in levels of TNFalpha and IL-1beta, the mechanisms that mediate ozone effects in asthma and in allergen-induced AHR remain unknown. Preliminary data shows that ozone and allergen in combination markedly increased airway neutrophils, baseline airway tone, AHR and KCl-induced airway smooth muscle (ASM) force generation, suggesting in part a direct effect on ASM excitation-contraction coupling. We postulate that O3 enhances allergen-induced AHR in mice by promoting neutrophil-mediated airway inflammation and by directly increasing agonist-induced ASM force generation. To test these hypotheses, in Aim 1, the role of neutrophils, TNFalpha and IL-1beta in mediating ozone-enhanced allergic AHR and airway inflammation will be determined using strategies to deplete or augment airway neutrophils and/or cytokines. Lung resistance and Penh will measure AHR and airway inflammation will be assessed in bronchoalveolar lavage by characterizing cell profiles and levels of cytokines and chemokines.
In Aim 2, using human ASM cells and murine tracheal rings from allergen-and ozone-treated wild type and knockout mice, the effects of ozone on critical ASM excitation-contraction coupling pathways will be defined. These essential pathways include ozone effects on agonist-induced: calcium responses, phosphoinositide metabolism and calcium sensitization processes of RhoA/RhoA kinase activation and of myosin light chain phosphatase inhibition. The sufficiency and necessity of each agonist-induced signaling event in mediating ozone and allergen effects on ASM cell function or on tracheal ring force generation will be determined. These studies will identify the mechanisms by which ozone enhances allergen-induced AHR and provide insight into new therapeutic targets to prevent asthma exacerbations and decrease asthma morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL080676-01
Application #
6923090
Study Section
Special Emphasis Panel (ZHL1-CSR-P (F1))
Program Officer
Noel, Patricia
Project Start
2005-05-01
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$452,685
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Damera, G; Fogle, H W; Lim, P et al. (2009) Vitamin D inhibits growth of human airway smooth muscle cells through growth factor-induced phosphorylation of retinoblastoma protein and checkpoint kinase 1. Br J Pharmacol 158:1429-41
Damera, Gautam; Tliba, Omar; Panettieri Jr, Reynold A (2009) Airway smooth muscle as an immunomodulatory cell. Pulm Pharmacol Ther 22:353-9
Damera, Gautam; Zhao, Hengjiang; Wang, Miao et al. (2009) Ozone modulates IL-6 secretion in human airway epithelial and smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 296:L674-83

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