Alcohol and airways function in health and disease

Abstract

The volatility of alcohol promotes the movement of alcohol from the bronchial circulation across the airway epithelium and into the conducting airways of the lung. The exposure of the airways through this route likely accounts for many of the biologic effects of alcohol on lung airway functions. The effect of alcohol on lung airway functions is dependent on the concentration, duration, and route of exposure. Brief exposure to mild concentrations of alcohol may enhance mucociliary clearance, stimulates bronchodilation, and probably attenuates the airway inflammation and injury observed in asthma and chronic obstructive pulmonary disease (COPD). Prolonged and heavy exposure to alcohol impairs mucociliary clearance, may complicate asthma management, and likely worsens outcomes including lung function and mortality in COPD patients. Nonalcohol congeners and alcohol metabolites act as triggers for airway disease exacerbations especially in atopic asthmatics and in Asian populations who have a reduced capacity to metabolize alcohol. Research focused on the mechanisms of alcohol-mediated changes in airway functions has identified specific mechanisms that mediate alcohol effects within the lung airways. These include prominent roles for the second messengers calcium and nitric oxide, regulatory kinases including PKG and PKA, alcohol- and acetaldehyde-metabolizing enzymes such as aldehyde dehydrogenase 2. The role alcohol may play in the pathobiology of airway mucus, bronchial blood flow, airway smooth muscle regulation, and the interaction with other airway exposure agents, such as cigarette smoke, represents opportunities for future investigation.

Figure 1. Acute and chronic effects of alcohol on airway cilia function

Upper panel: Brief exposure to modest concentrations of alcohol stimulates airway ciliated cell nitric oxide synthase (NOS) to produce nitric oxide (NO), activate guanylyl cyclase (GC) to produce cGMP, which activates a cGMP-dependent kinase (PKG) to phosphorylate a specific ciliary protein (pp28). In parallel, alcohol activates adenylyl cyclase isoform 7 (AC7) to produce cAMP, which activates a cAMP-dependent kinase (PKA) to phosphorylate another specific ciliary protein (pp29). The dual activation of these kinases by alcohol results in stimulation of ciliary beat frequency (CBF). Lower panel: Prolonged exposure to high concentrations of alcohol stimulates airway ciliated cell phosphodiesterase isoform 4 (PDE4) to degrade cAMP reducing ciliary beat frequency to pre-alcohol exposure levels. Concomitantly, alcohol desensitizes both the cGMP-dependent kinase (PKG) and the cAMP-dependent kinase (PKA) rendering these kinases resistant to activation. This dual kinase desensitization results in a the ciliated cell that is unresponsive to stimulation with beta agonists.

Figure 2. Effects of alcohol and related molecules on bronchial motor tone

Alcohol (pure ethanol), in the absence of any metabolites or congeners, relaxes airway smooth muscle tone resulting in bronchodilated airways. Non-alcohol congeners, often present in alcoholic beverages, can cause contraction of airway smooth muscle resulting in bronchoconstricted airways in some sensitized or allergic individuals. Acetaldehyde, the product of alcohol metabolism, can accumulate in individuals with genetically reduced aldehyde dehydrogenase isoform 2 deficiency (ALHD2), causing in bronchoconstricted airways resulting in “alcohol-induced bronchial asthma” (Shimoda et al., 1996).