Because increased airway smooth muscle (ASM) tone is an important contributor to airflow obstruction in asthma, our goal is to understand how signals transduced by beta2 adrenergic receptors (beta2AR) (which promote relaxation) and m2 muscarinic receptors (m2AChR) (which inhibit betaAR-mediated relaxation) are regulated in ASM. Recent studies have linked chronic use of betaAR agonists with increased asthma deaths, apparently via their effects on AH. Furthermore, decreased relaxation of ASM by betaAR agonists in vitro is associated with airway hyperresponsiveness (AH) and disease severity. Although the pathogenesis of AH and overt disease is thought to involve increased numbers of inflammatory cells in the lung, the relationship between inflammation, betaAR function, and AH is poorly understood. Preliminary Studies for this proposal indicate that inflammatory cytokines and betaAR agonists each up- regulate m2AChR and that stimulation of these receptors not only antagonizes the relaxant effects of betaAR agonists but also induces betaAR dysfunction by uncoupling the betaAR from adenylyl cyclase. Up- regulation of m2AChR is seen in the dog model of AH, but has never been investigated in human ASM. Hence, we hypothesize that interdependent regulation of m2AChR and betaAR cytokines, exogenous betaAR agonists, and endogenous cholinergic tone may contribute significantly to the deleterious effects of lung inflammation and betaAR agonist therapy. Using physiological, biochemical, and molecular techniques to study bovine, canine, and human ASM and the dog model of AH, we propose: a) to identify the biochemical mechanisms by which beta2AR activation increases expression of m2AChR and m2AChR activation uncouples beta2AR ; b) to identify the cellular pathways whereby TNFalpha alters beta2AR and m2AChR expression and function; c) to determine if the m2AChR pathway is up- regulated in ASM from humans with asthma; and d) to evaluate the importance of increased m2AChR expression in the exacerbation of AH by chronic in vivo treatment with BAR agonists. This study will provide important new information regarding beta2AR and m2AChR cross-regulation, will clarify the link between AH and inflammation, and will help to resolve the controversy about the use of betaAR agonists in chronic asthma therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045974-07
Application #
2392667
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1990-09-30
Project End
2000-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Social Sciences
Type
Schools of Arts and Sciences
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Schears, G; Clancy, J; Hirshman, C A et al. (1997) Chronic carbachol pretreatment decreases adenylyl cyclase activity in airway smooth muscle. Am J Physiol 273:L640-7
Emala, C W; Kuhl, J; Hirshman, C A et al. (1996) Rapid communication: cloning and sequencing of a canine beta 2-adrenergic receptor cDNA. J Anim Sci 74:2285
Emala, C W; Aryana, A; Levine, M A et al. (1995) Expression of muscarinic receptor subtypes and M2-muscarinic inhibition of adenylyl cyclase in lung. Am J Physiol 268:L101-7
Emala, C W; Aryana, A; Levine, M A et al. (1995) Basenji-greyhound dog: increased m2 muscarinic receptor expression in trachealis muscle. Am J Physiol 268:L935-40
Croxton, T L; Takahashi, M; Hirshman, C A (1994) Decreased ion transport by tracheal epithelium of the basenji-greyhound dog. J Appl Physiol 76:1489-93
McQuitty, C K; Emala, C W; Hirshman, C A et al. (1994) Polymorphism in the human beta 2 adrenergic receptor gene detected by restriction endonuclease digestion with Fnu4HI. Hum Genet 93:225
Lenox, W C; Hirshman, C A (1993) Amrinone attenuates airway constriction during halothane anesthesia. Anesthesiology 79:789-94
Sauder, R A; Lenox, W C; Tobias, J D et al. (1993) Methylprednisolone increases sensitivity to beta-adrenergic agonists within 48 hours in Basenji greyhounds. Anesthesiology 79:1278-83
Lindeman, K S; Hirshman, C A (1993) Corticosteroid withdrawal restores responses to calcium chelators and enhances cholinergic responsiveness. Am Rev Respir Dis 148:1581-5

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