Effects of β₂-adrenergic receptor overexpression on alveolar epithelial active transport

Abstract

β-Adrenergic receptor (βAR) agonists accelerate the clearance of edema from the alveolar airspace by increasing the function of epithelial transport proteins, including epithelial Na⁺ channels and Na,K-adenosinetriphosphatases. To improve our understanding of the role of the β₂AR in regulating alveolar fluid clearance, we used an adenoviral-mediated gene transfer strategy to effect significant increases in membrane-bound β₂AR number and function in the alveolar epithelium of normal rats. Alveolar fluid clearance in β₂AR-overexpressing lungs, measured by means of an isolated lung model in the absence of catecholamine supplementation, was 100% greater than in controls. These findings were associated with significant increases of epithelial Na⁺ channel function and Na,K-adenosine triphosphatase function in the peripheral lung. Experiments performed with adrenalectomized rats, a β₂-agonist (procaterol), and a nonspecific β-antagonist (propranolol) indicate that overexpression maximally up-regulates β₂-adrenergic-responsive alveolar fluid clearance and improves responsiveness to endogenous catecholamines. Mechanistic studies in human lung epithelial cells (A549) indicate that receptor overexpression prevents homologous receptor desensitization, possibly by overwhelming endogenous regulatory pathways. Our studies demonstrate that overexpression of β₂AR in lung epithelial cells can be used to study the role and regulation of alveolar β₂ARs. They also suggest a therapeutic role for the β₂AR in the treatment of pulmonary edema. (J Allergy Clin Immunol 2002;110:S242-6.)