Importantly, these abnormalities not only increase the risk of lung infections and injury, they cause worse morbidity and mortality in alcoholics compared to non-alcoholics. While there are no current therapies to combat these alcohol-induced pulmonary abnormalities, current research has revealed several important mechanisms that may be exploited to develop new treatment options for this vulnerable population. The mechanisms by which alcohol abuse impairs alveolar macrophage function have been evaluated in both experimental and human studies. While the exact mechanism responsible is not completely understood, it is likely that multiple processes contribute and act in concert. First, experimental models have consistently shown that alcohol is responsible for depletion of the antioxidant glutathione, which causes oxidative stress in the lung and impairs alveolar macrophage maturation and function (18).
During alcohol use, the AM response to remote injury and systemic oxidative stress renders the host susceptible to infection due to an over-exuberant, pro-inflammatory response that perpetuates even further systemic oxidative stress. In fact, some studies suggest that alcohol compromises host defenses against bacterial pneumonia, such as K. Pneumoniae, by suppressing the recruitment and bactericidal activity of polymorphonuclear leukocytes into the lung (Nelson et al., 1991) and attenuating lung expression of CXC chemokines bearing the Glu-Leu-Arg motif, which attracts T cells (Happel et al., 2007). There is high plasticity in AM activation that influences how alcohols effects on lung health and immunity pmc they clear microbes and respond to pathogens.
Similarly, Boe and colleagues (2001) found that alcohol-exposed rats had decreased pulmonary neutrophil recruitment for up to 18 hours following S. Pneumoniae challenge; after that, however, neutrophil recruitment remained elevated even 40 hours post-challenge compared with nondrinking rats. This observation suggests that in individuals with heavy alcohol exposure, the host neutrophils arrive late at the infected lung but stay longer (Sisson et al. 2005). Impaired neutrophil recruitment also has been reported in human volunteers with blood alcohol concentrations (BACs) of 0.10 percent and 0.24 percent (Gluckman and MacGregor 1978)—that is, even at BACs that only slightly exceed the threshold for legal intoxication in the United States (i.e., 0.08 percent).
The reads were aligned and quantified against the Mmul_8 rhesus macaque reference genome or the human genome GRCh38. A PCA was generated to determine the dimensionality of the data set and a UMAP was generated and cell clustering was performed. Differential gene expression analysis and functional enrichment were performed using MAST and Metascape, respectively (46). 1×106 live BAL cells were infected with SARS-CoV-2 (Washington isolate) at an MOI of 1 or left untreated for 24 hours at 37°C, 5% CO2.
The expression and function of both the Na/K-ATPase complexes and epithelial sodium channels are increased in the alveolar epithelium of alcohol-fed animals (Guidot et al. 2000; Otis et al. 2008). Thus, as long as there are no additional stresses, the alcoholic lung seems to be able to limit edema formation by upregulating salt and water transport across the epithelium, thereby compensating for the marked increase in the leakage of fluid between cells (i.e., paracellular leakage) into the airways. In the presence of an acute inflammatory stress, such as sepsis or aspiration, however, the paracellular leak increases dramatically, and the alveoli flood with proteinaceous edema fluid that overwhelms the already upregulated transepithelial pumping mechanisms. Although macrophages are derived from monocytes, the ability of AMs to be recruited into the alveolar space suggests that they represent a population of phagocytes present in this microenvironment that are very different from the resident macrophages of other tissues.
These novel observations have spawned considerable research endeavors examining the mechanisms by which alcohol abuse renders individuals susceptible to the development of both pneumonia and ARDS. These efforts have revealed that chronic alcohol ingestion causes increased oxidative stress, impaired immunity, and epithelial barrier dysfunction within the alveolar space. This review will focus on these mechanisms that contribute to what has been termed the “alcohol lung phenotype”. While alcoholism has many well-known medical consequences such as liver injury and pancreatitis, the effects of chronic alcohol exposure on the respiratory system are often overlooked. Specifically, studies have shown that alcohol abuse causes significant derangements in the lung and predisposes individuals to the development of pneumonia and acute lung injury. Several important processes are responsible for this increased susceptibility to pulmonary pathology, including alterations in nonimmunological defense systems, impairment of lung immunity, and alveolar epithelial barrier dysfunction.
Exceeding these daily or weekly drinking limits significantly increases the risk of developing AUD and problematic health outcomes (NIAAA 2014). Not only does the immune system mediate alcohol-related injury and illness, but a growing body of literature also indicates that immune signaling in the brain may contribute to alcohol use disorder. The article by Crews, Sarkar, and colleagues presents evidence that alcohol results in neuroimmune activation.
While the effect of alcohol on TNF-α production and release remains controversial, studies have illustrated that alcohol exposure reduces pulmonary expression of important TNF-regulated neutrophil chemokines and modifies intrinsic functions of the neutrophil itself (23). Specifically, Nrf2 function depends on adequate zinc levels, and alcohol interferes with the transporter molecules that mediate zinc absorption from the diet as well as its transport into the alveolar space (Joshi et al. 2009). The recognition that excessive chronic alcohol ingestion has such a dramatic and independent effect on the risk of acute lung injury prompted a search for the underlying mechanisms.
We are very excited to introduce this Special Issue of Alcohol devoted entirely to the subject of alcohol and its effects on lung injury and immune defense. This issue was made possible through the enthusiasm and support of Alcohol’s Editor-in-Chief, Dr. David M. Lovinger, who recognized the need for emphasizing the prominence of this growing area of alcohol research. Another potential therapeutic target is Nrf2, which can be activated by plant-derived compounds (i.e., phytochemicals), such as sulforaphane (Hybertson et al. 2011; Jensen et al. 2013). One clinical study (Burnham et al. 2012) evaluating the effects of 7-day treatment with the Nrf2 activator Protandim® in patients with AUD did not identify any significant improvement in glutathione levels or epithelial function.
While numerous alcohol research studies have focused on the brain and liver, the lung has been largely disregarded, by pulmonologists and alcohol researchers alike, as a key effector organ of alcohol use. By illuminating the key events and mechanisms of alcohol-induced immune activation or suppression, research is yielding deeper insights into alcohol’s highly variable and sometimes paradoxical influences on immune function. The insights summarized in this issue of ARCR present researchers and clinicians with opportunities to devise new interventions or refine existing ones to target the immune system and better manage alcohol-related diseases. Meadows and Zhang discuss specific mechanisms through which alcohol interferes with the body’s immune defense against cancer. They note, too, that a fully functioning immune system is vital to the success of conventional chemotherapy. The clinical management of all of these conditions may be more challenging in individuals who misuse alcohol because of coexisting immune impairment.
In addition to this flawed type-1 (Th1) response, the lungs of alcohol-fed rodents exhibit increased amounts of the inflammatory cytokine IL-10, which also may contribute to impaired lung clearance because normalizing IL-10 levels within the pulmonary system improves bacterial lung clearance (Greenberger et al. 1995). The respiratory tract has a sophisticated immune defense mechanism that effectively protects lungs from chemical insults, and from bacterial or viral infections. However, excess alcohol consumption suppresses the immune defense network and predisposes the respiratory tract to a range of infections (Macgregor and Loubia, 1997).
However, alcohol’s effects on neutrophil phagocytosis and pathogen killing are less clear than the effects on neutrophil recruitment, and the findings to date are inconclusive. Thus, some studies indicate that alcohol has no effect on neutrophil phagocytosis or pathogen killing (Nilsson et al. 1996; Spagnuolo and MacGregor 1975), whereas other studies demonstrate that acute alcohol exposure impairs functional activities of neutrophils. For example, Davis and colleagues (1991) found that alcohol-fed rats failed to clear bacteria from the lungs and had increased mortality.
Using the same model of intoxication and burn in which mice are deficient in TLR4 but not TLR2, IL-6 production and organ damage are attenuated after alcohol intoxication and burn injury compared to wild-type mice (Bird, Zahs, et al., 2010). Although much of the attention concerning lung infections in people with AUD has been focused on bacterial infections, these individuals also have an increased susceptibility to viral airway infections. RSV is one of the most common lower respiratory tract viral pathogens and is a major cause of respiratory infections in children. Although RSV infections once were thought to be limited to children, it is now clear that RSV also is a serious problem in older people, patients with chronic obstructive pulmonary disease (COPD), and people with AUD. Prolonged alcohol exposure alters the first line of the innate cellular defense, the mucociliary apparatus, against invading pathogens such as RSV.
by 
