Abstract
Chronic alcohol consumption is associated with increased incidence of ICU-related morbidity and mortality, primarily from acute respiratory distress syndrome (ARDS). However, the mechanisms involved are unknown. One explanation is that alcohol regulates epithelial sodium channels (ENaC) via oxidant signaling to promote a pro- injury environment. We used small rodent models to mimic acute and chronic alcohol consumption and tested the hypothesis that ethanol (EtOH) would affect lung fluid clearance by up-regulating ENaC activity in the lung. Fluorescence labeling of rat lung slices and in vivo mouse lung revealed an increase in ROS production in response to acute EtOH exposure. Using western blots and fluorescein-5-maleimide labeling, we conclude that EtOH exposure modifies cysteines of α-ENaC while data from single channel patch clamp analysis confirm that 0.16% EtOH increased ENaC activity in rat alveolar cells. In vivo lung fluid clearance demonstrated a latent increase in fluid clearance in mice receiving EtOH diet. Ethanol mice given a tracheal instillation of LPS demonstrated early lung fluid clearance compared to caloric control mice and C57Bl/6 mice. Standard biochemical techniques reveal that chronic EtOH consumption resulted in greater protein expression of the catalytic gp91phox subunit and the obligate Rac1 protein. Collectively these data suggest that chronic EtOH consumption may lead to altered regulation of ENaC, contributing to a ‘pro-injury’ environment in the alcohol lung.
Highlights
Chronic alcohol consumption is associated with an increased incidence of ICU-related morbidity and mortality, primarily due to acute respiratory distress syndrome (ARDS) [1,2]
ARDS is a severe form of acute lung injury characterized by inflammation, edema and diffuse alveolar damage that results in impaired gas exchange, release of pro-inflammatory cytokines and the development of oxidative stress [3]
In order to determine whether acute EtOH exposure can induce oxidative stress in lung epithelia, we measured the levels of Reactive Oxygen Species (ROS) production using Amplex Red and dihydroethidium (DHE) acutely following 0.16% EtOH application and in vivo using an acute EtOH model
Summary
Chronic alcohol consumption is associated with an increased incidence of ICU-related morbidity and mortality, primarily due to acute respiratory distress syndrome (ARDS) [1,2]. ARDS is a severe form of acute lung injury characterized by inflammation, edema and diffuse alveolar damage that results in impaired gas exchange, release of pro-inflammatory cytokines and the development of oxidative stress [3]. Lung edema is resolved by active salt and water transport. Epithelial sodium channels (ENaC) function to reabsorb sodium from the alveolar airway lumen and transport sodium into the cytosol where it is extruded by the ATPase pump. Sodium reabsorption leads to the development of an electrochemical gradient between the apical and basolateral cell membranes. The electrochemical gradient facilitates the osmotically driven reabsorption of water and the subsequent resolution of lung edema
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