In an unusual paradox, asthmatics that are chronically treated with bronchodilating beta-agonist medications such as albuterol, ventolin, and salbutamol may ultimately develop increased sensitivity to airway constriction and experience exacerbation of their condition. A new study by Stephen Liggett and colleagues at the University of Cincinnati in the August 15 issue of the Journal of Clinical Investigation describes a responsible mechanism for this adverse reaction and reveals a potential new therapeutic target in the treatment of asthma.
Inhaled selective beta-agonists are the most widely used treatment for the acute relief of asthma symptoms. Administered to asthmatic patients via an inhaler, nebulizer, in tablet or liquid form, or injection, they cause airway relaxation and reduced airway responsiveness to nonspecific contractile stimuli. This is achieved by drug binding to the beta2-adrenergic receptor (beta2AR). Despite the ability of these agents to immediately reverse airway obstruction, there has been ongoing concern that the use of these drugs may be associated with harmful outcomes. Some, but not all, studies have revealed that regular scheduled use (e.g., multiple times daily, every day) of inhaled beta-agonists has resulted in a loss of control over the condition, which can manifest as longer asthmatic attacks and and post-treatment airway hyperresponsiveness.
To date, the evidence has suggested that a desensitization of the beta2AR is responsible. Liggett and colleagues suggest an alternative explanation. The authors demonstrate that persistent high-level activation of the beta2AR leads to increased expression of phospholipase C-beta (PLC-beta) in airway smooth muscle, inducing a crosstalk between beta2AR signaling pathways that ultimately results in airway hyperresponsiveness.
In their accompanying commentary, Stephanie Shore and Jeffrey Drazen from the Harva
Contact: Brooke Grindlinger
Journal of Clinical Investigation