The incidence of asthma is increasing worldwide with a 250% increase in the US over the past 20 years. In 2001 the NIH estimated that 17 million Americans suffer from asthma and 12.1 million from COPD. An increasing number of patients with these diseases require anesthesia and bronchospasm especially during induction and emergence from anesthesia carries significant morbidity. A better understanding of therapies that minimize bronchospasm during anesthesia will make anesthetic care safer for a growing number of patients with asthma and COPD. Intubation of the trachea during induction or the presence of an endotracheal tube during emergence from anesthesia initiates a neurally-mediated irritant reflex in the airway promoting bronchoconstriction. Neural control of airway tone is modulated by both cholinergic nerves traveling within the vagus nerve and by nocioceptive C fibers that send afferent signals to the CMS that modulate cholinergic outflow and locally release tachykinins into the airway wall. In brain, tachykinins release v-amino butyric acid (GABA), the primary neuronal inhibitory neurotransmitter. The cholinergic component of this reflex has been extensively explored in animal models and humans but little is known regarding the contribution of C fibers, released tachykinins or GABA to reflex-induced bronchoconstriction. Propofol is known to allosterically enhance the activity of GABA at GABAA receptors in the brain and is recognized as the intravenous anesthetic induction agent of choice in patients at risk for bronchospasm but its mechanism of airway protection is poorly understood. Elucidating the mechanisms of propofol's protective airway effects may provide novel therapies for bronchoconstriction from many causes. Exciting preliminary data demonstrate that [1] GABA is locally present near airway smooth muscle, [2] airway smooth muscle expresses GABAA receptors, [3] GABAA agonists relax airway smooth muscle and [4] propofol selectively attenuates NK2-mediated airway constriction via GABAA receptors. Based on these preliminary data we hypothesize that airway irritation releases tachykinins which activate NK2 receptors on airway nerves to release GABA which allows for the allosteric potentiation at airway smooth muscle GABAA receptors by propofol to facilitate relaxation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065281-08
Application #
7857898
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2002-04-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
8
Fiscal Year
2010
Total Cost
$326,750
Indirect Cost
Name
Columbia University (N.Y.)
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Forkuo, Gloria S; Guthrie, Margaret L; Yuan, Nina Y et al. (2016) Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments. Mol Pharm 13:2026-38
Brown, Amy; Danielsson, Jennifer; Townsend, Elizabeth A et al. (2016) Attenuation of airway smooth muscle contractility via flavonol-mediated inhibition of phospholipase-Cβ. Am J Physiol Lung Cell Mol Physiol 310:L747-58
Yocum, Gene T; Gallos, George; Zhang, Yi et al. (2016) Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction. Am J Respir Cell Mol Biol 54:546-53
Danielsson, Jennifer; Zaidi, Sarah; Kim, Benjamin et al. (2016) Airway Epithelial Cell Release of GABA is Regulated by Protein Kinase A. Lung 194:401-8
Gallos, George; Yocum, Gene T; Siviski, Matthew E et al. (2015) Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling. Am J Physiol Lung Cell Mol Physiol 308:L931-42
Danielsson, Jennifer; Perez-Zoghbi, Jose; Bernstein, Kyra et al. (2015) Antagonists of the TMEM16A calcium-activated chloride channel modulate airway smooth muscle tone and intracellular calcium. Anesthesiology 123:569-81
Clayton, Terry; Poe, Michael M; Rallapalli, Sundari et al. (2015) A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model. Int J Med Chem 2015:430248
Mizuta, Kentaro; Zhang, Yi; Mizuta, Fumiko et al. (2015) Novel identification of the free fatty acid receptor FFAR1 that promotes contraction in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 309:L970-82
Danielsson, Jennifer; Yim, Peter; Rinderspacher, Alison et al. (2014) Chloride channel blockade relaxes airway smooth muscle and potentiates relaxation by β-agonists. Am J Physiol Lung Cell Mol Physiol 307:L273-82
Townsend, Elizabeth A; Zhang, Yi; Xu, Carrie et al. (2014) Active components of ginger potentiate *-agonist-induced relaxation of airway smooth muscle by modulating cytoskeletal regulatory proteins. Am J Respir Cell Mol Biol 50:115-24

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