Abstract

Asthma is characterized by airway obstruction, airway hyperresponsiveness (AHR) and airway inflammation. The medications used for control and acute relief of asthma may vary in effectiveness and produce serious side effects. Also, -30% of asthma patients do not achieve optimal control with any of the (SS (/) Quo ?<0 model of asthma, we have shown that chronic (28 day) administration of 13-blockers decreased AHR and produced broad anti-inflammatory effects, including dramatic changes in airway epithelium: reduced mucous production, improved morphology and increased production of I32ARs. These data suggest that the airway epithelium may be a key target affected by chronic 13-blocker therapy. Also, in a small clinical trial treating 10 mild asthmatics with the non-selective 13-blocker, nadolol, there was a dose-dependent increase in the P020 methacholine that resulted in a change of>two doubling doses in patients treated with 40 mg of nadolol. Our long-range goal is to develop 13-blockers as an alternative therapy for asthma. To make progress towards this translation, we need to understand their mechanisms of action. In this project, we will test the """"""""-w ?'_E Off' :.(n ECM (II :.. O-0 o-- (Q' 6C' 0-:

Public Health Relevance

The relevance of this project is that it could lead to new safer and more effective drugs for the treatment of asthma. Furthermore, the results could alter our understanding of asthma at a paradigm-shifting level.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079236-02
Application #
7924010
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Togias, Alkis
Project Start
2009-09-01
Project End
2012-04-14
Budget Start
2010-09-01
Budget End
2012-04-14
Support Year
2
Fiscal Year
2010
Total Cost
$341,444
Indirect Cost

  Institution

Name
University of Houston
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204

  Publications

Nguyen, Long P; Al-Sawalha, Nour A; Parra, Sergio et al. (2017) ?2-Adrenoceptor signaling in airway epithelial cells promotes eosinophilic inflammation, mucous metaplasia, and airway contractility. Proc Natl Acad Sci U S A 114:E9163-E9171
Penn, Raymond B; Bond, Richard A; Walker, Julia K L (2014) GPCRs and arrestins in airways: implications for asthma. Handb Exp Pharmacol 219:387-403
Alfaro, Victoria Y; Goldblatt, David L; Valverde, Gabriella R et al. (2014) Safety, tolerability, and biomarkers of the treatment of mice with aerosolized Toll-like receptor ligands. Front Pharmacol 5:8
Thanawala, Vaidehi J; Forkuo, Gloria S; Stallaert, Wayne et al. (2014) Ligand bias prevents class equality among beta-blockers. Curr Opin Pharmacol 16:50-7
Nguyen, Long P; Singh, Bhupinder; Okulate, Adedoyin A et al. (2012) Complementary anti-inflammatory effects of a ?-blocker and a corticosteroid in an asthma model. Naunyn Schmiedebergs Arch Pharmacol 385:203-10
Bond, Richard A; Giles, Heather (2011) For the love of paradox: from neurobiology to pharmacology. Behav Pharmacol 22:385-9
Walker, J K L; Penn, R B; Hanania, N A et al. (2011) New perspectives regarding ýý(2) -adrenoceptor ligands in the treatment of asthma. Br J Pharmacol 163:18-28
Dickey, Burton F; Walker, Julia K L; Hanania, Nicola A et al. (2010) beta-Adrenoceptor inverse agonists in asthma. Curr Opin Pharmacol 10:254-9
Lin, Rui; Peng, Hui; Nguyen, Long P et al. (2008) Changes in beta 2-adrenoceptor and other signaling proteins produced by chronic administration of 'beta-blockers'in a murine asthma model. Pulm Pharmacol Ther 21:115-24