Asthma, which is characterized by chronic airway inflammation, repeated episodes of reversible airway obstruction and airway hyper-reactivity, is most often initiated by IgE-mediated responses following exposure to allergens. Patients with severe, recurrent asthma also have airway remodeling with increased airway smooth muscle (ASM), increased inflammatory cells and collagen deposition. Inflammation and airway hyperresponsiveness are key components of the allergen-induced inflammatory response, which results from the interaction of airway cells and inflammatory cells that release local mediators. Although anti-inflammatory agents and ?-adrenergic bronchodilators remain the primary treatment for chronic and acute episodes of bronchoconstriction, there is a great need for new therapeutic approaches. Mechanical strain imposed on the lungs during breathing is an important modulator of airway responsiveness in vivo. Previous studies from this project have shown that chronic mechanical strain (CMS) produced in vivo by imposing continuous positive airway pressure (CPAP) dramatically reduces airway reactivity in vivo. Lungs and airway tissues isolated from the CPAP-treated animals also exhibit lower responsiveness to bronchoconstrictors. This suppression of airway responsiveness by CMS also occurs in the presence of allergen induced inflammation. A small clinical trial was also performed in which adults with asthma treated with nocturnal CPAP for 1 week showed a significant reduction in airway reactivity. Whereas studies from this project have previously focused on the effects of CMS on airway contractility, exciting preliminary data suggest that CMS also suppresses synthetic responses of the airway tissues to inflammatory mediators. IL-13, a key mediator of airway inflammation in asthma, acts directly on ASM tissues to cause the synthesis of the eosinophil chemoattractant, eotaxin, and hypercontractility. Studies from this project showed that the imposition of CMS on isolated ASM tissues suppressed the IL-13 induced eotaxin synthesis and that CMS imposed on the lungs of mice in vivo suppressed airway responsiveness, and inhibited ASM contractility and the activation of IL-13 activated signaling molecules. This suggests that CMS is a potent modulator of both contractile and synthetic functions of ASM and led to the novel hypothesis that chronic strain may be effective as an inhibitor of airway inflammation and the resultant airway remodelling. In the proposed studies, isolated airway tissues and mouse models of asthma will be used to evaluate the inflammatory responses of ASM tissues and the molecular mechanisms by which CMS modulates their properties. The efficacy of CPAP as an inhibitor of airway hyperreactivity and airway inflammation in children with severe asthma will also be determined. Mechanical strain with CPAP may provide a novel therapy for asthma patients with atopic inflammatory processes, and may be particularly useful in children with severe asthma, as it could reduce the chronic use of corticosteroids, which are associated with long term complications such as growth impairment.

Public Health Relevance

There is a great need for new therapies that can mitigate the airway inflammation and hyperreactivity that is characteristic of asthma. These studies will evaluate the effectiveness of mechanical strain as a non- pharmacologic approach to suppress airway inflammation and hyperresponsiveness.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL048522-18
Application #
8695572
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Noel, Patricia
Project Start
1992-08-13
Project End
2018-03-31
Budget Start
2014-05-01
Budget End
2015-03-31
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Wu, Yidi; Huang, Youliang; Gunst, Susan J (2016) Focal adhesion kinase (FAK) and mechanical stimulation negatively regulate the transition of airway smooth muscle tissues to a synthetic phenotype. Am J Physiol Lung Cell Mol Physiol 311:L893-L902
Zhang, Wenwu; Huang, Youliang; Gunst, Susan J (2016) p21-Activated kinase (Pak) regulates airway smooth muscle contraction by regulating paxillin complexes that mediate actin polymerization. J Physiol 594:4879-900
Wu, Yidi; Gunst, Susan J (2015) Vasodilator-stimulated phosphoprotein (VASP) regulates actin polymerization and contraction in airway smooth muscle by a vinculin-dependent mechanism. J Biol Chem 290:11403-16
Zhang, Wenwu; Huang, Youliang; Wu, Yidi et al. (2015) A novel role for RhoA GTPase in the regulation of airway smooth muscle contraction. Can J Physiol Pharmacol 93:129-36
Xue, Z; Zhang, W; Desai, L P et al. (2013) Increased mechanical strain imposed on murine lungs during ventilation in vivo depresses airway responsiveness and activation of protein kinase Akt. J Appl Physiol (1985) 114:1506-10
Busk, Michael; Busk, Nancy; Puntenney, Paula et al. (2013) Use of continuous positive airway pressure reduces airway reactivity in adults with asthma. Eur Respir J 41:317-22
Xue, Z; Yu, Y; Gao, H et al. (2011) Chronic continuous positive airway pressure (CPAP) reduces airway reactivity in vivo in an allergen-induced rabbit model of asthma. J Appl Physiol 111:353-7
Desai, Leena P; Wu, Yidi; Tepper, Robert S et al. (2011) Mechanical stimuli and IL-13 interact at integrin adhesion complexes to regulate expression of smooth muscle myosin heavy chain in airway smooth muscle tissue. Am J Physiol Lung Cell Mol Physiol 301:L275-84
Majumdar, Arnab; Hantos, Zoltan; Tolnai, Jozsef et al. (2009) Estimating the diameter of airways susceptible for collapse using crackle sound. J Appl Physiol 107:1504-12
Xue, Z; Zhang, L; Liu, Y et al. (2008) Chronic inflation of ferret lungs with CPAP reduces airway smooth muscle contractility in vivo and in vitro. J Appl Physiol 104:610-5

Showing the most recent 10 out of 26 publications