Effect/alveolar beta2 adrenergic receptor overexpression

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION (provided by applicant): Pulmonary edema is cleared from the alveolus as a result of the active transport of Na+ out from the airspace by alveolar epithelial transport proteins. It has been observed that in some types of pulmonary edema these active clearance mechanisms are impaired. Thus, methods that improve alveolar active transport may prove useful for the treatment of this common condition. It has been reported that beta2-adrenergic agonists increase active Na about transport and alveolar liquid clearance (ALC) via beta2-Adrenergic Receptors (beta2 AR) and that prolonged use of f3-agonists decreases beta2AR expression in the alveolar epithelium. In preliminary data included in this proposal we have observed that pharmacologic doses of a beta2-agonist desensitize alveolar f beta2ARs and that alveolar beta2AR over expression increases ALC. These studies caused us to hypothesize that: 1) alveolar f32ARs are subject to agonist-induced loss of function (desensitization), 2) loss of receptor function attenuates catecholamine responsive alveolar solute transport, 3) and receptor over expression can positively affect these processes by altering receptor desensitization patterns and increasing the number of functional receptors in the cell membrane. To test these hypotheses we are proposing three inter related specific aims that integrate molecular techniques with physiologic studies to generate new insights into the role and regulation of alveolar beta2ARs: Specific Aim #1: To determine if alveolar beta2AR over expression can improve receptor function and catecholamine responsive ALC. Specific Aim #2: To test if alveolar beta AR's are desensitized by about agonists, if desensitization affects ALC, and if over expression attenuates receptor desensitization. Specific Aim #3: To test if beta2AR function is impaired in experimental models of lung injury and if receptor function can be improved via over expression in models of acute Lung injury. Cardiogenic and non-cardiogenic pulmonary edema affect millions of people each year causing substantial morbidity and mortality. Currently there exists no specific treatment for this life-threatening condition. The goal of this proposal is to improve our understanding of the interactions between alveolar beta2ARs and alveolar Na, K-ATPases, Na about channels and ALC. The experimental plan included in this proposal has been structured to allow us to test our hypotheses and develop novel therapies to improve alveolar beta2AR function and pulmonary edema clearance.