Alcohol and Lung Injury and Immunity

Functional experiments were performed to confirm that HSP90 is required for alcohol to stimulate cilia via a chaperone and translocation mechanism, likely involving intraflagellar transport (Simet, Pavlik, & Sisson, 2013b). Schematic illustration by which alcohol abuse increases the risk of pulmonary infection by impairing the innate and adaptive immunity. An alternative metabolism of ethanol is driven by fatty acid ester ethyl ester (FAEE) synthase, phospholipase D, sulfatase and glucuronidase, called as nonoxidative pathway, are also ubiquitous in the mammalian lungs (Aradottir et al., 2006; Lieber, 2004; Manautou and Carlson, 1991; Sharma et al., 1991; Zakhari, 2006).

Chronic Alcohol Intake Compromises Lung Immunity by Altering Immunometabolism in Humans and Mouse Models

• Animal model studies have recapitulated the increased severity of bacterial and viral infections with CHD further highlighting the immunological basis of these adverse outcomes (26, 27).
• This may increase alcohol consumption and risky decisionmaking and decrease behavioral flexibility, thereby promoting and sustaining high levels of drinking.
• Bailey et al. show that cannabis and alcohol use initiate the inflammatory cytokine response through up-regulation of toll-like receptors in the airway epithelium.
• Glutathione is the primary thiol antioxidant found in the alveoli; it serves an essential function in reactions catalyzed by the enzyme glutathione peroxidase, which clears harmful hydrogen peroxide and lipid hydroperoxides that readily form in the oxidizing environment of the lung.

In patients with alcohol use disorder (AUD), alterations occur in the tight junctions between alveolar epithelial cells so that protein-rich fluid from the blood can more easily traverse the interstitial tissue and enter the lumen of the alveoli that is normally dry. These and other changes in alveolar epithelial cells predispose people with AUD to developing acute respiratory distress syndrome (ARDS) that is characterized by pulmonary edema. IFN-γ–producing (i.e., type 1) T cells mediate immune reactions that are responsible for fighting not only M. Pneumoniae induces time-dependent release of IL-12 from T cells, which in turn drives T cell IFN-γ production. This chain of reactions is disrupted by alcohol, because the levels of both IL-12 and IFN-γ were decreased in alcohol-exposed mice infected with K.

Alcohol and Lung Injury and Immunity

Alcohol abuse is therefore a risk factor for active TB (Borgdorff et al. 1998; Buskin et al. 1994; Kline et alcohols effects on lung health and immunity pmc al. 1995; Narasimhan et al. 2013). In addition to the adverse implications for society, alcoholism has significant psychological, health, and social consequences for the individual. Pathological alcohol use has been linked to several mental health disorders such as depression, anxiety, and post-traumatic stress disorder (4). Beyond these psychological consequences, alcohol can elicit changes in virtually every organ system in the body due its small size and solubility in both water and lipids (5).

Figure 1.

Many proofs of concept experiments could be evaluated using primary cell culture and animal models exposed to ethanol compared to its oxidative and non oxidative metabolites. Moreover, alcohol metabolites can also act as triggers for airway disease exacerbations especially in atopic asthmatics and in Asian populations who are known to have a reduced capacity to metabolize alcohol. Therefore, epidemiological studies in larger cohorts would improve understanding of the effects of chronic alcohol abuse and metabolites of ethanol on the complement system. These disruptions to the composition of the gut microbiota and to gut barrier function have important implications beyond the intestinal system. For example, Nagy discusses how the leakage of bacterial products from the gut activate the innate immune system in the liver, triggering inflammation that underlies ALD, a condition that affects more than 2 million Americans and which eventually may lead to liver cirrhosis and liver cancer.

Alcoholism and pneumonia: effects on nonimmunological defenses in the airway

• An intriguing answer comes from recent studies showing that, at least in experimental models, chronic alcohol ingestion inhibits the expression and function of a protein called Nrf2.
• Taken together, these findings demonstrate that the airways—including the oral cavity and extending all the way to the alveolar space—are subjected to high concentrations of alcohol and its deleterious metabolites during intoxication.
• Although they hypothesized that alveolar macrophages from AUD vs. non-AUD subjects would respond differently to pneumococcal stimuli, no differences in inflammatory mediator release are observed.
• Curtis et al. report that intoxicated burn patients exhibit increased systemic inflammation, hepatic damage, and liver and lung apoptosis and inflammation; however, intravenous treatment with mesenchymal stem cells can mitigate alcohol-burn derangements.

With chronic alcohol ingestion, oxidative stress pathways in the AMs are stimulated, thereby impairing AM immune capacity and pathogen clearance. The epidemiology of pneumococcal pneumonia and AUDs is well established, as both increased predisposition and illness severity have been reported. AUD subjects have increased susceptibility to pneumococcal pneumonia infections, which may be due to the pro-inflammatory response of AMs, leading to increased oxidative stress. Given the multiple perturbations in the airway caused by alcoholism, individuals are vulnerable to aspiration and numerous pulmonary infections. Importantly, pneumonia and aspiration events are the most common direct causes of acute lung injury and ARDS (27). While this relationship may be one explanation for alcoholics’ increased risk for this syndrome, there is also experimental evidence that alcohol causes specific defects in the alveolar epithelium that leave the host susceptible to lung injury.

The role of these two signaling molecules is supported by the observation that treatment with recombinant GM-CSF can rapidly restore alveolar epithelial function in alcohol-fed rats, both in vivo and in vitro (Pelaez et al. 2004). Though not as well acknowledged, the organ that is perhaps most rapidly affected by chronic alcohol ingestion is the lung. While alcohol itself does not cause direct injury to the lung in a fashion similar to hepatic cirrhosis, chronic exposure to alcohol renders individuals susceptible to the development of pulmonary infections and lung injury. In fact, experimental studies have shown that these alcohol-induced pulmonary derangements occur in as little as six weeks of regular consumption (7).

Oxidative stress and ARDS and COPD

Also, as noted above, chronic alcohol ingestion interferes with Nrf2 signaling in alveolar macrophages (Mehta et al. 2011), thereby disrupting the expression of hundreds of genes that are crucial to combatting oxidative stress. Although the precise role of alcohol-mediated inhibition of the Nrf2–ARE pathway in mediating oxidative stress has not been completely clarified, this pathway represents a strategic target to direct future therapies. ARDS is a severe form of lung injury characterized by fluid accumulation in the lung that is not related to heart problems (i.e., noncardiogenic pulmonary edema) as well as by flooding of the alveolar airspaces with protein-like (i.e., proteinaceous) fluid (Ware 2006; Ware and Matthay 2000). ARDS develops in response to inflammatory stresses, including sepsis, trauma, gastric aspiration, pneumonia, and massive blood transfusions (Ware and Matthay 2000). Originally described by Ashbaugh and colleagues (1967), ARDS is characterized by alveolar epithelial and endothelial barrier disruption, dysfunction of the lipoprotein complex (i.e., surfactant) coating the lung surfaces, and intense inflammation. The alcohol-induced dysregulation of lung neutrophil recruitment and clearance is only part of the problem in people with AUD, because alcohol also has harmful effects on other aspects of neutrophil functioning.

Replacement IgG therapy only partially restored Ig levels in these people, although it decreased the rates of pulmonary infections (Spinozzi et al. 1992). In macaques, most immune cell populations decreased in relative frequency following six months of ethanol consumption, with the exception of AM. The increase in the relative frequency of AM was more pronounced in male macaques, which is in accordance with data from rodent models (55). Moreover, ethanol consumption led to a shift toward inflammatory AM and non-classical monocytes in line with heightened inflammation (3, 28, 51, 56). We also report that chronic ethanol consumption skews the immune landscape towards inflammatory responses, as indicated by increased expression of genes within the HIF1α as well as TLR signaling pathways. Despite the decreases in B cell numbers, alcoholics with liver disease have increased levels of circulating nonprotective IgA, IgM, and IgG.

The findings indicate that G-CSF can prevent alcohol-induced deficits in neutrophil-dependent pulmonary defenses by increasing neutrophil production and bacterial killing function. Although T cells were not the primary target of SARS-CoV-2 (Fig 1F), transcriptional responses to infection were noted (Supp. Fig 2C, D). DEGs that play a role in type I and II interferon and anti-viral pathways were more evident at baseline. Overall, these findings indicate that ethanol consumption skews the transcriptional profiles of alveolar cells towards a hyperinflammatory state while antiviral responses are dampened. In animals, dietary GSH supplementation is effective in maintaining GSH homeostasis, but it requires chronic GSH ingestion to prevent oxidative damage (Guidot and Brown, 2000; Guidot et al., 2000; Holguin et al., 1998).

Surfactant is a lipoprotein complex produced by alveolar cells that covers alveoli and helps ensure proper lung function. Delayed-type hypersensitivity responses are excessive immune reactions that occur only a few days after the body has been exposed to the pathogen. These responses are not mediated by immune molecules produced by B cells (i.e., antibodies) but by T cells. The epithelial cells line the alveolar surface that faces the inside (or airspace) of alveoli, whereas the endothelial cells line the surface that faces the outside of the alveoli and the surrounding blood vessels.

Toxicity of ethanol metabolites

Alcohol-induced alveolar macrophage dysfunction likely occurs primarily as a result of alcohol-induced increases in oxidative stress, which is reflected by depletion of the antioxidant glutathione (GSH) in BAL fluid (Brown et al. 2007; Yeh et al. 2007). Impaired secretion of granulocyte monocyte colony-stimulating factor (GM-CSF) by type II alveolar cells likely also contributes to alcohol-induced oxidative stress (Joshi et al. 2005). The experimental evidence that alcohol can cause a profound defect in the physical barrier of the alveolar epithelium led to the question of why alcohol abuse alone, in the absence of an acute stress such as sepsis, does not cause pulmonary edema. Additional studies revealed that alcohol causes a concurrent, and perhaps compensatory, increase in salt and water transport across the epithelium. This transport is mediated by specific epithelial sodium channels located in the apical membrane and by protein pumps (i.e., Na/K-ATPase complexes) in the basolateral membrane of the epithelial cells.

Alcohol abuse and endoplasmic reticulum (ER) stress in lungs

Experimental animal models of chronic alcohol ingestion demonstrated similar oxidation of the lung microenvironment. GSH levels were abrogated in the lungs and bronchoalveolar lavage (BAL) fluid of ethanol-fed rats (Holguin, Moss, Brown, & Guidot, 1998) and mice (Yeligar, Harris, Hart, & Brown, 2014). Collectively, these studies indicate that chronic alcohol abuse alters GSH homeostasis in the lung, leading to an increasingly oxidized pulmonary microenvironment.