Alcoholism Causes Alveolar Macrophage Zinc Deficiency and Immune Dysfunction

Abstract

Rationale: Alcohol use disorders cause oxidative stress in the lower airways and increase susceptibility to pneumonia and lung injury. Currently, no therapeutic options exist to mitigate the pulmonary consequences of alcoholism. Objectives: We recently determined in an animal model that alcohol ingestion impairs pulmonary zinc metabolism and causes alveolar macrophage immune dysfunction. The objective of this research is to determine the effects of alcoholism on zinc bioavailability and alveolar macrophage function in human subjects. Methods: We recruited otherwise healthy alcoholics (n ¼ 17) and matched control subjects (n ¼ 17) who underwent bronchoscopy for isolation of alveolar macrophages, which were analyzed for intracellular zinc, phagocytic function, and surface expression of granulocyte-macrophage colony-stimulating factor receptor; all three of these indices are decreased in experimental models. Measurements and Main Results: Alcoholic subjects had normal serum zinc, but significantly decreased alveolar macrophage intracellular zinc levels (adjusted means [SE] Conclusions: These novel clinical findings provide evidence that alcohol abuse is associated with significant zinc deficiency and immune dysfunction within the alveolar space and suggest that dietary supplementation with zinc and glutathione precursors could enhance airway innate immunity and decrease the risk for pneumonia or lung injury in these vulnerable individuals.Keywords: alcohol abuse; alveolar macrophage; zinc; immunity; glutathione Alcohol use and abuse are prevalent and impose significant health burdens in society. A recent national survey suggests that more than half of the population in the United States older than the age of 12 consumes alcohol (1) and the lifetime prevalence of alcohol abuse is 18% (2). Tragically, alcohol abuse is the third leading cause of preventable death in the United States (3), and alcoholism is associated with numerous chronic, nonfatal health implications. The overall annual cost of alcohol abuse to American society has been estimated to be upward of $200 billion (4).The consequences of alcoholism span multiple organ systems, including the heart, liver, brain, and skeletal muscle (5, 6). Among these widespread effects, alcohol abuse renders individuals susceptible to pulmonary infections and acute lung injury (7-10). We have explored potential mechanisms in experimental animal models and determined that chronic alcohol ingestion causes previously unrecognized cellular dysfunction and oxidative stress, as best reflected by significant decreases in glutathione (GSH) levels, within the alveolar space (11-14). Alveolar macrophages, which are the primary immune cell in the lower airways, exhibit impaired phagocytosis and respiratory burst generation in animal models of chronic alcohol ingestion (15, 16), and treatment with antioxidants reverses these defects (17, 18). In addition, we established that decreased signaling of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates alcohol-induced alveo...

Peroxisome Proliferator–Activated Receptor γ Regulates Chronic Alcohol-Induced Alveolar Macrophage Dysfunction

“…Subjects with alcoholism and control subjects without alcoholism were recruited (30). All human subjects provided written informed consent before study enrollment.…”

“…All human subjects provided written informed consent before study enrollment. Bronchoalveolar lavage (BAL) was performed (30) and human AMs (hAMs) were isolated (19,29). Selected cells were treated with 10 mM RSG (Cayman Chemicals, Ann Arbor, MI) or methylcellulose vehicle for 24 hours.…”

Impact of bacterial coinfection on clinical outcomes in pneumococcal pneumonia

“…Alcoholism causes alveolar macrophage zinc deficiency and immune dysfunction [29] and may increase the risk of a variety of infections. Patients with HCAP are often considered to be at greater risk for colonization and infection with a wider spectrum of multidrugresistant organisms than those with CAP [30], which might be a possible reason for risk for bacterial coinfection in pneumococcal pneumonia.…”

Effects of ethanol on RhoA/Rho-kinase-mediated calcium sensitization in mouse lung parenchymal tissue

“…Alcohol (ethanol) is involved in many deleterious effect on the respiratory system, such as respiratory distress syndrome (Moazed and Calfee, 2014), pneumonia (Chalmers et al, 2009;Mehta et al, 2013). The attenuation of smooth muscle contraction by ethanoltreatment have been demonstrated in several studies (Boselli and Govoni, 2000;Kesim et al, 2004;Verde et al, 2014).…”