Alcohols Effects on Lung Health and Immunity | TStudio

Brief exposure to moderate concentrations of alcohol stimulates cilia to beat faster through a nitric oxide-dependent mechanism (Sisson, Pavlik, & Wyatt, 2009). Conversely, prolonged alcohol exposure causes desensitization of cilia, making motility resistant to stimulation, a process known as alcohol-induced ciliary dysfunction (AICD), through a mechanism related to oxidant stress (Simet, Pavlik, & Sisson, 2013a; Wyatt, Gentry-Nielsen, Pavlik, & Sisson, 2004). While the mechanisms of alcohol-driven cilia stimulation and AICD are known to involve dysregulation of key cilia kinases and phosphatases that regulate motility, the upstream triggers of these post-translational processes are unknown. One mechanism may be through post-translational modifications in key kinases and phosphatases that regulate the effects of alcohol on airway ciliary control. Specifically, studies have focused on alcohol’s ability to modulate phosphorylation and S-nitrosylation of target molecular regulatory pathways in airway cilia, alcohols effects on lung health and immunity pmc thereby providing insight into the differential effects of brief versus prolonged alcohol exposure on the ciliated airway epithelium. Alcohol exacerbates post-burn levels of systemic pro-inflammatory cytokines, such as interleukin-6 (IL-6) (M. M. Chen, Palmer, et al., 2013; Colantoni et al., 2000; Li, Akhtar, Kovacs, Gamelli, & Choudhry, 2011), which can quickly accumulate in the pulmonary vasculature (M. M. Chen, Bird, et al., 2013).

For example, chronic alcohol ingestion has been shown to not only impair salivary gland secretion, but also the ability of saliva to appropriately buffer acid. These defects accelerate gingival disease, promote tooth decay, and encourage colonization of the mouth with gram-negative bacteria such as Klebsiella pneumonia (14). Still, under normal circumstances the lungs would be protected from these potential pathogens by various protective reflexes that prevent aspiration.

While the majority of literature emphasizes liver disease, pancreatitis, and central nervous system abnormalities as primary targets of alcohol consumption, there is a growing body of evidence that alcoholism causes significant derangements in the lung. Through a variety of mechanisms, chronic alcohol ingestion perturbs both immunological and nonimmunolgical host defense mechanisms within the airway that result in alveolar macrophage immune dysregulation and alveolar epithelial barrier dysfunction. These important defects render alcoholic individuals susceptible to the development of pneumonia and ARDS. While there are no currently approved treatments for the alcohol lung phenotype, current research efforts are continuing to uncover several potential therapeutic strategies for this vulnerable population as they continue to try and work through their disabling addiction. One of the central features of ARDS is an impaired barrier function of the alveolar epithelial and endothelial cells.3 Studies on the effect of alcohol alone on alveolar barrier function have revealed that chronic alcohol intake alters physical barrier properties within alveoli (Guidot et al. 2000). Interestingly, alveolar cells from ethanol-fed rats had increased expression of sodium channels in the membrane facing the interior of the alveoli (i.e., the apical membrane).

As is the case with other organs, alcohol’s specific effects on the conducting airways depend on the route, dose, and length of the exposure (Sisson 2007).
Furthermore, comparative transcriptomics analysis using lungs and liver samples from matched human and mouse subjects demonstrated that lungs were more sensitive than liver to the effects of alcohol in downregulating immune-related genes and pathways.
Further, studies show that exposure to alcohol not only decreases lymphocyte count, it also diminishes lymphocyte response to stimulation (26).
For example, it has been recognized for over a century that alcoholics are at increased risk for infection with Mycobacterium tuberculosis.
In addition to neutrophil recruitment to infected areas and reduced neutrophil-killing potential, production of these cells also is affected.

ARDS

BAL cells were thawed, stained with the specified antibodies, acquired using an Attune NxT Flow Cytometer, and analyzed using the FlowJo software.

Metabolism of alcohol in the lungs

While the mechanism by which alcoholics are predisposed to tuberculosis is not fully understood, there are significant alcohol-induced abnormalities in the number and function lymphocytes. Specifically, alcoholism has been shown to cause generalized lymphopenia, especially in patients with chronic liver disease (25). Further, studies show that exposure to alcohol not only decreases lymphocyte count, it also diminishes lymphocyte response to stimulation (26). Taken together, these findings highlight that chronic exposure to alcohol causes dysregulation of all aspects of lung immunity in the lower airway, including innate immune reactions as well as the adaptive immune response and cell-mediated immunity.

Alcohol-induced failure of the mucociliary system could interfere with the clearance of pathogens from the airways and thereby may contribute to the increased risk of pulmonary infections in people with chronic heavy alcohol use (Sisson 2007). These combined studies suggest that alcohol-induced gut leakiness and liver macrophage activation may drive cytokine expression, resulting in systemic oxidative stress and lung injury. This lung injury starts with the desensitization of the ciliated airway epithelium, causing impaired clearance of inhaled pathogens from the upper airway. Altered activation of alcoholic alveolar macrophages in the lower airway not only impairs bacterial phagocytosis and clearance, but may also induce the release of more cytokines into the circulation. Kupffer cells, resident liver macrophages, demonstrate up-regulation of pro-inflammatory transcription factors and pathways, including hypoxia inducible factor-1 alpha and activator protein-1 (Yeligar, Machida, & Kalra, 2010).

Precisely, one animal study demonstrated that lung edema is much more pronounced in response to endotoxin among alcohol-fed rats compared to control-fed rats (28). Further, when alveolar epithelial cells are isolated and cultured from animals that chronically ingest alcohol, they are much more permeable compared to epithelial cells cultured from non-alcoholic animals (7). Taken together, these studies illustrate that alcohol abuse gives rise to significant derangements in alveolar epithelial barrier function that cause increased permeability, and analogous to the pathogenesis of ARDS, edematous injury will only occur in response to a stressor. Studies also have analyzed the role of GM-CSF in alcohol-induced oxidative stress and impaired lung immunity. GM-CSF is secreted by type II alveolar cells and is required for terminal differentiation of circulating monocytes into mature, functional alveolar macrophages (Joshi et al. 2006). Conversely, overexpression of GM-CSF in genetically modified (i.e., transgenic) mice causes increased lung size, excessive growth (i.e., hyperplasia) of alveolar epithelial cells, and improved surfactant protein removal from the alveolar space (Ikegami et al. 1997).

Dietary supplementation of GSH precursors can also restore both the mitochondrial and cytosolic GSH pool, as well as alveolar epithelial functions and can significantly decrease the risk of alcoholic lung injury (Guidot and Brown, 2000). Therefore, adequate GSH precursor supplementation, which might significantly decrease risk of alcoholic lung injury and possibly even pneumonia, should be a better therapeutic approach. Studies in to the etiology of lung diseases like COPD and idiopathic lung fibrosis indicate a role for ER stress and unfolded protein response (UPR) pathways in their pathogenesis (Greene and McElvaney, 2010; Malhotra and Kaufman, 2007). Clearly, as with all alcohol-related health issues, the ideal treatment would be abstinence in people with underlying AUD and/or a safe level of consumption in people who choose to drink for social reasons. However, this ideal will be impossible to achieve in any meaningful timeframe and it therefore is critical to identify, test, and validate therapeutic strategies that can limit the morbidity and mortality of alcohol-related diseases, including acute lung injury and pneumonia. Alcohol induces aberrant transforming growth factor beta1 (TGFβ1) expression in the alveolar epithelium and thereby dampens signaling through the granulocyte/macrophage colony-stimulating factor (GM-CSF)–PU.1 and Nrf2–antioxidant responsive element (ARE) signaling pathways.

Alcohol abuse and endoplasmic reticulum (ER) stress in lungs

When inhaled pathogens are not cleared in the upper airway, they enter the alveolar space, where they are phagocytized and cleared by AMs.
This injury results in leakage of proteinaceous fluid into the normally dry alveolar spaces, causing a significant impairment in gas exchange.
CYP2E1 is particularly induced during chronic alcohol abuse and is shown to be responsible for production of reactive oxygen species (Lieber, 2004).
At low levels, cytokines, such as IL-6, are beneficial to hepatocyte survival, but exposure to levels above an acceptable threshold can be detrimental (Jin et al., 2006).

Circulating cytokines may further perpetuate systemic oxidative stress that results from alcohol-use disorders. This cycle of systemic oxidative stress and the effects it may have on the gut-liver-lung axis have been summarized in Fig. Acute and chronic alcohol intoxication interferes with the innate response at structural and barrier levels causing leakiness between the physical barriers and mucosal organs, increased lung permeability due compromised tight junctions between the epithelial cells, and reduced cell mediated host defense mechanisms. Chronic alcohol consumption disrupts lung immunity and host defense mechanisms, rendering individuals with alcohol use disorder more susceptible to developing inflammatory lung conditions with poor prognoses.

Alcoholism and pneumonia: effects on lung immunity

Although alveolar macrophages are the primary residential innate immune cells and play a pivotal role in the clearance of bacterial and viral pathogens, understanding of and research on their specific function in the context of heavy alcohol consumption and AUD still is lacking. It is clear, however, that prolonged alcohol consumption alters the pathophysiology and key factors involved in neutrophil-driven lung immunity in response to S. Thus, studies have shown that exposure to alcohol impairs neutrophil recruitment (Gluckman and MacGregor 1978), weakens phagocytosis of pathogens by neutrophils (Boe et al. 2001; Jareo et al. 1995), and reduces neutrophil production and release of neutrophils into circulating blood (Melvan et al. 2011; Siggins et al. 2011).

Lungs as target of alcohol-induced oxidative stress

Therefore, strategies to reverse any of these mechanisms for alcohol-induced exaggerated oxidative stress in the AM may improve lung immune function and susceptibility to developing respiratory infections in patients with a history of AUDs. The AM is acutely affected by chronic alcohol ingestion and the oxidized lung microenvironment that results from alcohol abuse. Through multifactorial mechanisms, alcohol stimulates oxidative stress within the AM, resulting in impaired phagocytic capacity and decreased bacterial clearance. Experimental manipulations of each of these mechanisms attenuated alcohol-induced oxidative stress and improved AM immune function. In 1789, Dr. Benjamin Rush, the first surgeon general of the United States, observed that individuals with an affinity for alcohol had a higher incidence of pneumonia and tuberculosis (Rush, 1808). In 1885, Sir William Osler reported that alcohol is one of the greatest predisposing factors to the development of pneumonia (Osler, 1892).

Alcohol and Lung Injury and Immunity

Experimental models demonstrate that restoration of GM-CSF signaling reverses this alcohol-induced dysfunction (Joshi et al. 2005), suggesting that this might be a potential therapeutic approach. Also, as mentioned earlier, recent evidence suggests that interactions exist between Nrf2 and the GM-CSF pathway, with Nrf2 regulating the expression and activity of the transcription factor PU.1, which controls GM-CSF expression (Staitieh et al. 2015). Understanding the complex interplay between all of these systems in the alcoholic lung will become exceedingly important in the search for new and effective treatments. Another fundamental mechanism that appears to drive many of the pathophysiological manifestations of the alcoholic lung phenotype is a severe depletion of glutathione stores within the alveolar space.

Interestingly, Nrf2 also regulates the expression of PU.1, a master transcription factor that mediates GM-CSF–dependent signaling (Staitieh et al. 2015). Accordingly, alcohol-induced reduction of Nrf2 also inhibits binding of PU.1 to its nuclear targets, which can be improved by zinc treatment (Mehta et al. 2011). Thus, alcohol impairs epithelial barrier function in the lung through a complex set of mechanisms with several cycles and feedback mechanisms (see figure 2); however, future studies will almost certainly elucidate further details. Another key function of the alveolar epithelium, namely the synthesis and secretion of surfactant—which is required to maintain alveolar integrity and gas exchange—also is impaired by chronic alcohol ingestion (Holguin et al. 1998).

This impairment can lead to sepsis and pneumonia and also increases the incidence and extent of postoperative complications, including delay in wound closure. Bagby and colleagues review substantial evidence that alcohol further disrupts the immune system, significantly increasing the likelihood of HIV transmission and progression. Therefore, clinical investigations should carefully characterize these potential confounders to most accurately study the effect of alcohol on outcome variables since these confounders have the potential to contribute to the heterogeneity of human AM populations and phenotype plasticity. Further study in suitably powered populations is warranted to delineate and characterize heterogeneous AM populations and their phenotypes in individuals with alcohol-use disorders. Two approaches to explore protein changes in alcohol-exposed isolated bovine tracheal cilia were developed.

However, these alcohol-fed rats had diminished airway clearance when challenged with saline, even in the absence of an inflammatory challenge (Guidot et al. 2000). These data suggest that the alveolar epithelium actually is dysfunctional after alcohol exposure, even though it seems normal and is able to regulate the normal air–liquid interface by enhancing sodium channels at the apical surface. In the presence of an inflammatory reaction, the compensatory mechanism likely becomes overwhelmed, resulting in greater susceptibility to barrier disruption and flooding of the alveolar space with protein-containing fluid. Although the interrelationship between oxidative stress and antioxidants is not fully explored in alcoholic lung injury, reduced GSH appears to be a determining factor in human and experimental models of alcoholic lung disease (Guidot and Roman, 2002). To maintain normal physiological redox status, GSH, which is synthesized primarily in the liver, is circulated to all other organs including the lungs.