Author: John Carter

How Alcohol Affects Lung Cancer Risk and Outcomes

Animal studies have shown that chronic alcohol exposure causes significant alveolar macrophage dysfunction, leaving these normally active immune cells poorly equipped to phagocytose or kill invading organisms (Brown et al. 2009; Joshi et al. 2009). Alveolar macrophages in alcohol-exposed animals also exhibit decreased production of important chemokines and mediators, which impairs their ability to recruit other cell types, namely neutrophils, during times of stress and infection (Happel et al. 2004). Although the majority of data focuses on the effects of chronic alcohol ingestion, experimental evidence further suggests that even acute exposure has similar detrimental effects on alveolar macrophage immune function, although these defects readily resolve (Libon et al. 1993). Taken together, these alcohol-mediated defects in alveolar macrophage function contribute to increased vulnerability to pulmonary infections.

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. In this particular study, pulmonary inflammation in alcohol-exposed mice persisted for more than 7 days after infection, compared with 3 to 5 days in the control animals. These results corroborate findings that infection in the setting of alcohol exposure increases the risk of complications such as ARDS. 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).

Alcohol and Asthma

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. 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. 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 both experimental animal models and humans, chronic alcohol ingestion causes a profound decrease of up to 80 percent to 90 percent in alveolar glutathione levels (Holguin et al. 1998; Moss et al. 2000). This glutathione depletion cannot be explained by dietary deficiency or smoking because it also occurs in experimental animals with an otherwise sufficient diet (Holguin et al. 1998); moreover, otherwise healthy smokers actually have increased glutathione levels within their alveolar space (Moss et al. 2000). Further analyses in experimental models found that alcohol-induced glutathione depletion seems to mediate the defects in alveolar epithelial barrier function.

They speculated that the difference in alcohol clearance was likely related to concomitant medication use or hypoxia and hypercapnea which can cause micosomal enzyme induction in the liver of the asthmatic patients that increased alcohol metabolism. The most recent study of intravenous ethanol on airflow examined the changes in spirometry, lung volumes and airway conductance that followed infusion of three different concentrations of ethanol (2%, 4% and 8% v/v in saline) in 5 normal subjects and 5 atopic asthmatics (Ayres and Clark, 1983b). While no change in any pulmonary function was noted in the normal subjects at any concentration of IV alcohol, concentration-dependent bronchodilation occurred in all of the asthmatics. At the highest concentration (8%) IV alcohol caused a 33% increase in airway conductance in the asthmatics, which was roughly one third of the response that inhaled salmeterol, a beta-agonist, could induce in the same patients.

Thus, although the total number of circulating B cells does not differ significantly between people with and without AUD, people with AUD have elevated levels of circulating IgA, IgM, and IgG (Spinozzi et al. 1992). In the lungs of people with AUD, however, Ig levels are reduced as determined by bronchoalveolar lavage (BAL) (Spinozzi et al. 1992). Replacement IgG therapy only partially restored Ig levels in these people, although it decreased the rates of pulmonary infections (Spinozzi et al. 1992).

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. Collectively, these derangements encompass what has been termed the “alcoholic lung” phenotype. Alcohol-related reductions in antioxidant levels also may contribute to lung disease in people with underlying AUD.

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). 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).

Alcohol Use and Lung Cancer Survival

At the highest concentration of IP alcohol used (21%) clearance was slowed five-fold compared to control mice and there was a strong direct correlation between the reductions of airway clearance with the blood alcohol concentrations. Importantly, in the same study the investigators directly observed tracheal clearance of inert carbon particles following IP alcohol injection of anesthetized kittens. Alcohol caused a rapid and reversible concentration-dependent slowing of airway particle clearance compared to control kittens. While the focus of these experiments was mucociliary clearance, the impact of alcohol on mucus production was not examined. Diseases of the conducting airways are extremely common with prominent examples including bronchitis, asthma and chronic obstructive pulmonary disease (COPD).

1. Therefore, the experimental findings to date implicate the pathophysiological sequence in the alcoholic lung shown in figure 2.
2. When a patient with pneumonia is an alcoholic, the mortality rate exceeds by 50% if they are placed into intensive care (ICU).
3. This point was made in a small but elegant study by Breslin in 1973 of eleven subjects with asthma who reported worsening of their asthma symptoms following the ingestion of an alcoholic beverage (Breslin et al., 1973).
4. This hypothesis is further supported by an animal study that determined that aerosolized acetaldehyde but not ethanol induced histamine-mediated bronchoconstriction in guinea pigs (Myou et al., 1994).

Although these animal models provide convincing evidence implicating glutathione depletion as a mediator of alveolar epithelial barrier dysfunction, additional studies in humans are necessary to confirm these findings. As discussed in this review, genetic analysis has helped to identify potential candidate genes involved in alcohol-induced lung dysfunction that might explain the newly identified association between alcohol abuse and acute lung injury in humans. Although several genes of interest were identified and pursued as has been discussed, the vast majority of the genes that displayed significantly altered expression in the alcohol-fed rat lung have not yet been evaluated.

Potential Mechanisms by Which Alcohol Abuse Increases Risk for Acute Lung Injury

Although there are several treatment strategies being researched for alcoholic lung damage, the most effective way to prevent further lung damage is to stop drinking. Acute respiratory distress syndrome (ARDS) is a severe type of lung injury that in many cases can be deadly. The most common causes include a buildup of fluid in the lungs, severe pneumonia, or another major injury.

This study suggests that while alcohol can immediately trigger an initial small upper airway irritant response, a separate slow bronchodilator effect can be observed in asthmatics. Clinicians and physiologists commonly believe that the alcohol present in exhaled air during alcohol consumption comes from alcohol that is vaporized from the alveolar-capillary interface of the pulmonary circulation. Careful studies by George and colleagues show that almost all of the exhaled alcohol is derived from the bronchial and not the pulmonary circulation (George et al., 1996). During alcohol ingestion, alcohol freely diffuses from the bronchial circulation directly through the ciliated epithelium where it vaporizes as it moves into the conducting airways (George et al., 1996). Indeed, alcohol vapor excreted into the airways in this manner forms the basis of the breath test used to estimate blood alcohol levels (Hlastala, 1998).

At this point it is safe to say that our knowledge about the influence of inhaled alcohol on airway function is unsatisfactory. 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 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. 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.

Alcohol and Mucociliary Clearance

Research also suggests that alcohol use can influence morbidity and mortality (illness and death) in people with lung cancer. Contributing to this phenomenon is a person’s perception of wellness following cancer treatment. There has been debate about the nature of this relationship, with some studies arguing that there is no association and others contending that alcohol may have a protective benefit in certain cases. Glucocorticoids are often used for managing chronic lung conditions, while antibiotics are used to treat bacterial lung infections.