Chronic ethanol ingestion impairs alveolar type II cell glutathione homeostasis and function and predisposes to endotoxin-mediated acute edematous lung injury in rats.

Abstract

Chronic alcohol abuse increases the incidence and mortality of the acute respiratory distress syndrome (ARDS) in septic patients. To examine a potential mechanism, we hypothesized that ethanol ingestion predisposes to sepsis-mediated acute lung injury by decreasing alveolar type II cell glutathione homeostasis and function. Lungs isolated from rats fed ethanol (20% in water for >/= 3 wk), compared with lungs from control-fed rats, had greater (P < 0. 05) edematous injury (reflected by nonhydrostatic weight gain) after endotoxin (2 mg/kg intraperitoneally) and subsequent perfusion ex vivo with n-formylmethionylleucylphenylalanine (fMLP, 10(-7) M). Ethanol ingestion decreased (P < 0.05) glutathione levels in the plasma, lung tissue, and lung lavage fluid, and increased (P < 0.05) oxidized glutathione levels in the lung lavage fluid. Furthermore, ethanol ingestion decreased type II cell glutathione content by 95% (P < 0.05), decreased (P < 0.05) type II cell surfactant synthesis and secretion, and decreased (P < 0.05) type II cell viability, in vitro. Finally, treatment with the glutathione precursors S-adenosyl-L-methionine and N-acetylcysteine in the final week of ethanol ingestion significantly reduced lung edema during perfusion ex vivo. We conclude that ethanol ingestion in rats alters alveolar type II cell glutathione levels and function, thereby predisposing the lung to acute edematous injury after endotoxemia. We speculate that chronic alcohol abuse in humans predisposes to ARDS through similar mechanisms.

Zinc Deficiency Mediates Alcohol-Induced Alveolar Epithelial and Macrophage Dysfunction in Rats

“…Zinc also plays a role in the regulation of cellular glutathione (29) and protects cell membranes from oxidative damage (30). This is particularly intriguing, as we have published extensively on the role of oxidant stress and glutathione depletion in experimental models of chronic alcohol ingestion and in human subjects with alcohol abuse (5,7,(31)(32)(33)(34). Therefore, alcohol-induced zinc deficiency may play a central role in the oxidant stress and consequent cellular dysfunction that has been shown to characterize the alcoholic lung phenotype.…”

“…Our research group has determined that chronic alcohol ingestion in experimental animals as well as in otherwise healthy individuals has profound effects on airway epithelial and macrophage function (4)(5)(6)(7)(8)(9). Specifically, the epithelial barrier within the small gas-exchanging airways, the alveoli, is compromised.…”

Pathophysiology of Acute Lung Injury and the Acute Respiratory Distress Syndrome

“…134,135 In rats, chronic feeding with ethanol reduces levels of glutathione in lung tissue, lung lavage fluid, and alveolar epithelial type II cells. 136 Chronic ethanol feeding also increased the severity of both endotoxin-induced and cecal ligation and puncture-induced lung injury. 136,137 In humans, individuals who chronically abuse alcohol but are otherwise healthy have lower levels of glutathione and a higher percentage of oxidized glutathione in bronchoalveolar lavage fluid compared with controls.…”

“…136 Chronic ethanol feeding also increased the severity of both endotoxin-induced and cecal ligation and puncture-induced lung injury. 136,137 In humans, individuals who chronically abuse alcohol but are otherwise healthy have lower levels of glutathione and a higher percentage of oxidized glutathione in bronchoalveolar lavage fluid compared with controls. 138 Patients with ARDS who abuse alcohol also have decreased levels of glutathione in bronchoalveolar lavage fluid compared with normal controls.…”

Alcohol Ingestion by Donors Amplifies Experimental Airway Disease after Heterotopic Transplantation

“…Using animal models of alcoholism, studies have shown that alcohol ingestion primes the lung for injury (18)(19)(20) and increases transforming growth factor (TGF)-b 1 in the lung (21,22). Clinically, subjects with alcoholism increased risk of acute respiratory distress syndrome after stresses, such as sepsis or trauma (23,24).…”