Chronic alcohol ingestion changes the landscape of the alveolar epithelium

Abstract

Similar to effects of alcohol on the heart, liver, and brain, the effects of ethanol (EtOH) on lung injury are preventable. Unlike other vital organ systems, however, the lethal effects of alcohol on the lung are underappreciated, perhaps because there are no signs of overt pulmonary disorder until a secondary insult, such as a bacterial infection or injury, occurs in the lung. This paper provides overview of the complex changes in the alveolar environment known to occur following both chronic and acute alcohol exposures. Contemporary animal and cell culture models for alcohol-induced lung dysfunction are discussed, with emphasis on the effect of alcohol on transepithelial transport processes, namely, epithelial sodium channel activity (ENaC). The cascading effect of tissue and phagocytic Nadph oxidase (Nox) may be triggered by ethanol exposure, and as such, alcohol ingestion and exposure lead to a prooxidative environment; thus impacting alveolar macrophage (AM) function and oxidative stress. A better understanding of how alcohol changes the landscape of the alveolar epithelium can lead to improvements in treating acute respiratory distress syndrome (ARDS) for which hospitalized alcoholics are at an increased risk.

Figure 1

Chronic ethanol ingestion changes the landscape of the alveolar epithelium. 40X original magnification of white light illumination of trichrome-labeled cryoslices obtained from maltoedextrin-fed (control; top) versus chronic EtOH-fed mouse lung (Meadows-Cook model; bottom). (*) indicates inflamed area with exudate. Arrow points to alveolar macrophages inside airway. Note collapsed airway in Meadows-Cook alcohol mouse model versus control-fed animal.

Figure 2

Overview of the complex interplay between cells and proinflammatory mediators which might orchestrate the pathogenesis of acute lung injury. We propose that chronic alcohol abuse disrupts the lung epithelium and activates tissue Nox enzymes, producing low levels of H₂O₂, which can diffuse to nearby blood vessels and chemoattract phagocytes. Asterisks indicate causal connection established between alveolar Nox activity and lung ENaC. In the alcohol lung, phagocytes have elevated Nox1, Nox2, and Nox4 activity, which oxidizes the extracellular milieu and alters normal cell function. Because of ongoing drug discovery efforts in developing more sensitive and specific Nox inhibitors, studying the role of Nox enzyme in alcohol-related lung injury is important. Because the alcohol lung is more susceptible to infection and injury, studying the intimate relationship between AM and epithelial transport is important.