Chronic-Alcohol-Abuse-Induced Oxidative Stress in the Development of Acute Respiratory Distress Syndrome

Abstract

Chronic alcohol ingestion increases the risk of developing acute respiratory distress syndrome (ARDS), a severe form of acute lung injury, characterized by alveolar epithelial and endothelial barrier disruption and intense inflammation. Alcohol abuse is also associated with a higher incidence of sepsis or pneumonia resulting in a higher rate of admittance to intensive care, longer inpatient stays, higher healthcare costs, and a 2–4 times greater mortality rate. Chronic alcohol ingestion induced severe oxidative stress associated with increased ROS generation, depletion of the critical antioxidant glutathione (GSH), and oxidation of the thiol/disulfide redox potential in the alveolar epithelial lining fluid and exhaled breath condensate. Across intracellular and extracellular GSH pools in alveolar type II cells and alveolar macrophages, chronic alcohol ingestion consistently induced a 40–60 mV oxidation of GSH/GSSG suggesting that the redox potentials of different alveolar GSH pools are in equilibrium. Alcohol-induced GSH depletion or oxidation was associated with impaired functions of alveolar type II cells and alveolar macrophages but could be reversed by restoring GSH pools in the alveolar lining fluid. The aims of this paper are to address the mechanisms for alcohol-induced GSH depletion and oxidation and the subsequent effects in alveolar barrier integrity, modulation of the immune response, and apoptosis.

Chronic ethanol exposure alters the lung proteome and leads to mitochondrial dysfunction in alveolar type 2 cells

“…In line with our previous studies (7,33), our present findings indicate that a large number of the differentially expressed proteins in the alcohol lung are related to mitochondrial dysfunction.…”

“…Alcohol-induced oxidative stress has also been shown to play a pivotal role in acute lung injury (17,33). In particular, subcellular ethanol-induced oxidation is reflected in organelles where there is a ϩ60-mV increase in oxidation of the GSH/GSSG redox potential in the mitochondria of alveolar type 2 cells (33). Significant changes in the alcohol lung's ability to maintain alveolar fluid homeostasis have also been reported.…”

“…For example, it has only been recently appreciated that intracellular zinc levels in alveolar macrophages are significantly attenuated in chronic alcoholics, despite normal serum zinc bioavailability (39). Alcohol-induced oxidative stress has also been shown to play a pivotal role in acute lung injury (17,33). In particular, subcellular ethanol-induced oxidation is reflected in organelles where there is a ϩ60-mV increase in oxidation of the GSH/GSSG redox potential in the mitochondria of alveolar type 2 cells (33).…”

“…Serious changes in the lung proteome of alcoholics are often masked, given that the effects of chronic alcohol ingestion remain benign until secondary injury occurs (40 -42). Despite recent significant advances made in understanding the etiology of alcohol-related disorders (7,14,17,33), the molecular mechanisms that predispose alcoholics to acute respiratory distress syndrome are complex and remain unclear. For example, it has only been recently appreciated that intracellular zinc levels in alveolar macrophages are significantly attenuated in chronic alcoholics, despite normal serum zinc bioavailability (39).…”

Glutathione attenuates ethanol-induced alveolar macrophage oxidative stress and dysfunction by downregulating NADPH oxidases

“…One mechanism could be through restoration of the GSH pool, as shown in the studies presented herein, or cysteine pool in the AM. By breaking down extracellular GSH, ␥-glutamyltransferase (GGT) provides cysteine, the rate-limiting amino acid for GSH resynthesis (45). As such, GGT is critical for maintaining GSH and cysteine homeostasis.…”