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.
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