Acute mechanical strain imposed on the lungs during breathing is well known to be an important modulator of airway responsiveness in vivo;however, the changes in airway reactivity with acute mechanical strain are transient, lasting only for a few minutes. Our laboratory has recently demonstrated that chronic mechanical strain produced by imposing continuous positive airway pressure (CPAP) on rabbit lungs in vivo for 4-5 days results in a dramatic reduction in airway responses to bronchoconstrictor challenge in vivo. In addition, we observed that the effect of chronic strain was present in the muscle isolated from the in vivo treated animals, indicating that the reduction in airway responsiveness in vivo can primarily be attributed to alterations in the airway smooth muscle. Our studies have demonstrated that maintaining isolated airways and isolated strips of tracheal smooth muscle in culture for several days under conditions of mechanical strain alters the passive and contractile properties of these tissues. The airways and tracheal smooth muscle tissues become larger, more compliant, and exhibit a decreased contractile response to stimulation compared to tissues maintained in culture not under mechanical strain. In isolated strips of tracheal smooth muscle, we have demonstrated that integrin-mediated signaling pathways are important in the transduction of external mechanical signals to the cytoskeletal signaling proteins. We hypothesize that chronic strain imposed on the airways modulates airway properties by stimulating mechano-sensitive signals that regulate the activity of cytoskeletal proteins that control the actin cytoskeleton and contractile apparatus. We propose to evaluate mechanisms by which chronic mechanical strain decreases airway responsiveness. In addition, we will evaluate the potential of chronic mechanical strain as a novel therapeutic intervention in patients with airways hyper-reactivity, which may have important implications for the therapeutic modulation of airway reactivity early in life.
The specific aims of this project are to:1) Determine whether the effect of chronic mechanical strain on airway reactivity is modulated by the pattern of chronic mechanical strain, as well as the presence of heightened airway reactivity;2) Determine whether chronic nocturnal CPAP decreases airway reactivity in clinically stable patients with asthma;3) Evaluate the molecular mechanisms for the effects of chronic mechanical strain on the physiologic and structural properties of airway smooth muscle. PROJECT NARRATIVE. Patients with asthma have airways that are very sensitive to stimulation and their airways narrow more than non-asthma subjects when stimulated. We have demonstrated that applying chronic stretch to the lung can decrease airway reactivity in animals, as well as in isolated airways. Our study will evaluate the mechanisms for how chronic stretch of the lung can decrease the sensitivity of airway narrowing and evaluate whether this approach can provide a novel treatment for patients with asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048522-17
Application #
8303413
Study Section
Special Emphasis Panel (ZRG1-RES-C (02))
Program Officer
Noel, Patricia
Project Start
1992-08-13
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
17
Fiscal Year
2012
Total Cost
$388,499
Indirect Cost
$120,026
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
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