A pairwise comparison of the relative abundance of clusters after infection showed a significantly reduced frequency of the AM3, AM5, and DC clusters and a notable decrease in the AM7, Mono, CD4, and CD8 clusters at baseline (Figure 1D). After 6 months of ethanol consumption, significant decrease in frequency was evident in AM1 and CD4 clusters, with a notable decrease in the Mono cluster and an increase in the Epithelial cluster was observed in response to SARS-CoV-2 infection (Figure 1D). Additionally, this analysis revealed that myeloid clusters contained a majority of the SARS-CoV-2 transcript, with the AM7 cluster exhibiting the greatest expression (Figure 1F,G). Interestingly, the average expression of SARS-CoV-2 transcripts was significantly decreased across all AM clusters, except AM4 and AM5, after 6 months of ethanol consumption (Figure 1G). In contrast, levels of viral transcripts were increased in the CD4 and CD8 T cell subset after 6 months of chronic ethanol consumption (Figure 1G). Cell mediated adaptive immunity is another important aspect of host defense which can be impaired by alcohol and its metabolites (Fig. 3).
Unraveling the alcohol-pneumococcal pneumonia relationship: clues from translational research
These alterations included suppression of genes responsible for fatty acid metabolism in the lungs of the alcohol-exposed rats, which caused accumulation of triglycerides and free fatty acids in the distal airspaces and resulted in immune dysfunction of the alveolar macrophages. In another model using mice, Yeligar and colleagues (2012) demonstrated that alcohol induced oxidative stress through the upregulation of specific enzymes called NADPH oxidases, which are an important source of oxidants called reactive oxygen species in alveolar macrophages. A similar pattern of NADPH upregulation existed in human alveolar macrophages isolated from people with AUD. Restoring the redox balance in the lung could reverse many of these alcohol-induced defects and improve alveolar macrophage immune function (Brown et al. 2007; Yeligar et al. 2014).
- 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.
- The potential influence of alcohol consumption on airway health and disease has been documented for a long time.
- Brief and prolonged alcohol exposure drive different post-translational modifications of novel proteins that control cilia function.
- NK cells do not need previous exposure to their target cells to recognize, bind to, and destroy these targets (e.g., cancer and virus-infected cells) (Vivier et al. 2008).
Chronic ethanol consumption alters transcriptional response to SARS-CoV-2
Among the many organ systems affected by harmful alcohol use, the lungs are particularly susceptible to infections and injury. The mechanisms responsible for rendering people with alcohol use disorder (AUD) vulnerable to lung damage include alterations in host defenses of the upper and lower airways, disruption of alveolar epithelial barrier integrity, and alveolar macrophage immune dysfunction. Alcohol-related reductions in antioxidant levels also may contribute to lung disease in people with underlying AUD.
SARS-CoV-2 Infection
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). More recent studies have established that biologically relevant alcohol concentrations have very focused and specific effects on the lung airways. Over the past two decades, studies demonstrated that brief exposure to modest alcohol concentrations triggers generation of nitric oxide (NO) in the airway epithelial cells. This NO production stimulates a signaling pathway that involves the enzyme guanylyl cyclase, which produces a compound called cyclic guanosine monophosphate (cGMP). CGMP, in turn, activates cGMP-dependent protein kinase (PKG), followed by activation of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA).
Unlike previous chronic alcohol feeding models in mice, this chronic-binge model results in elevated lung lavage neutrophils and subsequent change in lung function. These results suggest that alcohol alone can differentially impact airway function based upon the nature of consumption. The potential influence of alcohol consumption on airway health and disease has been documented for a long time. Chronic alcohol ingestion constantly subjects the drinker’s airways to high concentrations of alcohol vapor, as best evidenced by the use of alcohol breath tests (i.e., Breathalyzer). The volatile nature of alcohol is exploited in this common field sobriety test, which is reliably used as a surrogate to quantify blood alcohol concentrations.
Mechanisms of Alcohol’s Effects on Alveolar Macrophages
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. These studies underscore the complexities of translating pre-clinical findings to humans and demonstrate the critical importance of continuing such studies in the future. Myeloid cells were also the predominant cell type to harbor SARS-CoV-2 transcripts in BAL samples from humans with AUD. However, inflammatory mediators were produced at greater levels in samples from individuals with AUD compared to the control smoking group only. This differs from the data obtained with NHP control BAL samples which were obtained before beginning of ethanol self-administration, suggesting that smoking may abrogate inflammatory responses. Indeed, previous work has shown that tobacco smoking reduces both gene expression and production of proinflammatory cytokines (TNFα, IL-1β, and IL-16) in alveolar macrophages stimulated with TLR2 and TLR4 agonists (71).
- Ciliated airway cells clear inhaled particles from the lung, thus acting as the first line of defense against inhaled pathogens.
- Pneumococcal pneumonia, caused by the bacterium Streptococcus pneumoniae, is the most common type of pneumonia in both healthy individuals and heavy alcohol users (Ruiz et al. 1999).
- AICD likely results from decreased HSP90/eNOS association, which in turn attenuates the NO-stimulated cGMP/cAMP-dependent kinase activation pathway (Simet et al. 2013a; Wyatt and Sisson 2001).
- Following 6 months of ethanol self-administration, the frequency of CD8 T cells was significantly reduced in females while that of natural killer (NK) cells was significantly reduced in males (Supp. Figure 1C, E).
- However, ROS-derived reactions with endogenous biomolecules are often complex and multifaceted, resulting in the generation of secondary and tertiary reactive products and causing dimerization and polymerization between and among the radicals and adducts.
In an attempt to explain some of these discrepancies, Breslin and colleagues (1973) compared the effects of exposure to different types of alcohol in a clinical study. These analyses found that whereas pure alcohol did not appear to induce bronchial reactivity, some alcoholic beverages worsened asthma symptoms. These findings were the first to suggest that the nonalcohol components and additives of alcoholic beverages may be responsible for inducing asthma, rather than alcohol itself. Similar findings were seen in later studies that examined the effects of red wine in asthma (Dahl et al. 1986; Vally et al. 2000). However, researchers have not yet been able to determine conclusively if alcohol ingestion has any clinically significant effects on asthma. For example, Bouchard and colleagues (2012) showed that alcohol exposure triggered asthma-like pulmonary inflammation in an allergen-sensitized mouse model.
Chronic alcohol ingestion depletes reduced GSH within the alveolar space by as much as 80–90%, and, consequently impairs alveolar epithelial surfactant production and barrier integrity, decreases alveolar macrophage function, and increases lung susceptibility to oxidant-mediated injury. Alcohol administration also increases glutathione turnover, a process independent of glutathione oxidation, glutathione S-transferase (GST) and glutathione peroxidase (GPX) activities. This risk further is exacerbated by the negative effects of chronic alcohol ingestion on the lower airways. In particular, animal models have established that chronic excessive alcohol ingestion causes dysfunction of the mucociliary apparatus, an important host defense mechanism responsible for clearing harmful pathogens and mucus from the lower airways (Happel and Nelson 2005). An early experimental study in sheep investigating the effects of alcohol on ciliary beat frequency (CBF) demonstrated a dose-dependent effect, such that low alcohol concentrations actually stimulated CBF, whereas high concentrations impaired it (Maurer and Liebman 1988). Later mechanistic studies found that whereas short-term alcohol exposure causes a transient increase in CBF, chronic exposure desensitizes the cilia so that they cannot respond to stimulation (Wyatt et al. 2004).
Other countries also report similar TB treatment defaults in individuals with AUD, resulting in poorer treatment outcomes and increased mortality rates (Bumburidi et al. 2006; Jakubowiak et al. 2007). Along with noncompliance, people with AUD have compromised lymphocytes, which are among the main immune components combating TB infections. Chronic alcohol intake modulates the functions of all three of these lymphocyte populations (Cook 1998; Lundy et al. 1975; Meadows et al. 1992; Spinozzi et al. 1992; Szabo 1999). Whether any particular long term therapeutic strategy will be effective for either alcoholic lung disease, ARDS or COPD cannot be predicted with certainty. Though dietary supplementation with GSH precursors or selective inhibition of ACE II and/or AT receptors can limit lung injury in animal models, G-CSF appears to be most attractive candidate for treating the alcoholic lung disease as well as for ARDS and COPD. In this study, alcohol-mediated compromise to barrier function is studied in both the lung epithelium and vascular endothelium in response to lipopolysaccharides (LPS).
This recycling of alcohol vapor continually subjects the conducting airways to high concentrations of alcohol (George et al. 1996), which modify airway-epithelium host defenses by altering cytokine release, barrier function (Simet et al. 2012), and cilia function (Sisson 1995; Sisson et al. 2009; Wyatt and Sisson 2001). Although TB is treatable with antibiotics, the prevalence of multidrug-resistant tuberculosis (MDRTB) is on the rise and has been reported worldwide (WHO 2014). One of the main factors increasing the prevalence of MDRTB is noncompliance alcohols effects on lung health and immunity pmc by patients who do not complete their normal 6-month treatment regimen, leading to the emergence of drug-resistant M. A recent study of MDRTB in South Africa reports that of 225 patients diagnosed with MDRTB, only 50 percent were cured or completed treatment.
The majority of ingested ethanol is metabolized in the liver by cytosolic alcohol dehydrogenase (ADH) to acetaldehyde, which is further oxidized by mitochondrial aldehyde dehydrogenase (ALDH) to acetate (Lieber, 2004). Mammalian lungs can metabolize ingested ethanol by ADH followed by ALDH at rates dependent on its concentration (Bernstein, 1982; Jones, 1995; Qin and Meng, 2006; Vasiliou and Marselos, 1989; Yin et al., 1992). Ethanol can also be metabolized by microsomal cytochrome P450 2E1 (CYP2E1) and peroxisomal catalase to acetaldehyde in both the liver and in lungs (Bernstein et al., 1990; Jones, 1995; Rikans and Gonzalez, 1990; Yin et al., 1992). CYP2E1 is particularly induced during chronic alcohol abuse and is shown to be responsible for production of reactive oxygen species (Lieber, 2004).
Finally, interplay between the B-cells and T-cells is required for optimal immune responses to counteract the invasion of most the pathogens. This review first will discuss key aspects of the epidemiology and pathophysiology of AUD and lung health, before focusing more in-depth on lung infections and acute lung injury, which comprise the majority of alcohol-related lung diseases. The article also will briefly review some of the experimental therapies that hold promise for decreasing the enormous morbidity and mortality caused by the “alcoholic lung” in our society. In contrast to brief alcohol exposure, prolonged alcohol exposure completely desensitizes lung airway cilia such that they can no longer beat faster when exposed to inhaled pathogens. In AICD, prolonged alcohol exposure results in failure to stimulate CBF, thereby desensitizing cilia to activating agents such as beta agonists (Wyatt and Sisson 2001).