Alcohol consumption in mice reduces the in vitro killing capacity of NK cells compared with control animals not exposed to alcohol (Meadows et al. 1992). Pretreatment with G-CSF ameliorates alcohol-induced neutrophil dysfunction, including impairments in neutrophil recruitment and bacterial killing. One of the most common and deadliest conditions afflicting individuals with AUD is bacterial pneumonia.
Alcohol abuse and endoplasmic reticulum (ER) stress in lungs
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). Conversely, the relative abundance of alveolar macrophages (AM) was increased in both males and females (Supp. Fig 1F). This increase was primarily mediated by an expansion of activated AM (CD163+), and a decrease in interstitial macrophages (IM) (Supp. Fig 1F, G). The frequency of dendritic cells (DC) also significantly increased after 6 months of CHD in males, whereas the opposite trend was observed in females (Supp. Fig 1H). The frequency of infiltrating monocytes was greater in females than males at baseline but decreased with drinking (Supp. Fig 1I). Nevertheless, ethanol exposure led to an expansion of nonclassical (activated) monocytes and a decrease in classical monocytes in both males and females (Supp. Fig 1I).
The precise mechanisms by which alcohol impairs alveolar macrophage immune function have yet to be elucidated; however, several observations indicate that the macrophages are subjected to an altered environment characterized by oxidative stress and zinc deficiency. Both clinical and experimental studies have detected increased oxidative stress in the alveolar space after alcohol exposure (Moss et al. 2000; Velasquez et al. 2002). The exact mechanisms responsible for inducing this redox imbalance remain uncertain, but several explanations have been put forth. An experimental rat model of chronic alcohol ingestion identified perturbations in lipid metabolism analogous to what is seen in alcohol-induced fatty liver (Romero et al. 2014).
Bacterial Pneumonia
This review investigates some of the potential mechanisms by which alcohol causes lung injury and impairs lung immunity. In intoxicated individuals with burn injuries, activation of the gut-liver axis drives pulmonary inflammation, thereby negatively impacting morbidity and mortality. In the lung, the upper airway is the first checkpoint to fail in microbe clearance during alcohol-induced lung immune dysfunction.
Mechanisms of Alcohol’s Effects on Alveolar Macrophages
Alcohol consumption also damages epithelial cells, T cells, and neutrophils in the GI system, disrupting gut barrier function and facilitating leakage of microbes into the circulation (see the article by Hammer and colleagues). 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). Tuberculosis infection and produce interferon γ (INF-γ), an important cytokine that stimulates cell-mediated immunity (Junqueira-Kipnis et al. 2003).
- 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).
- 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).
- Tuberculosis infection and produce interferon γ (INF-γ), an important cytokine that stimulates cell-mediated immunity (Junqueira-Kipnis et al. 2003).
- 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).
Additionally, in-vitro ethanol treatment of monocytes resulted in lower expression levels of MHC-II molecules (33), suggesting that CHD can lead to reduced antigen presentation capacity. Similarly, excessive alcohol consumption interferes with the phagocytic capacity of alveolar macrophages (AM) and their ability to generate anti-viral and anti-bacterial responses (34–36). Alcohol exposure in rats dampens the expression of GM-CSF receptors required for the differentiation of monocytes into macrophages upon infiltrating the lungs (34, 37). In addition to impairing immune responses, CHD decreases barrier function in the respiratory tract, increasing susceptibility to respiratory infections (38). Individuals with CHD are at increased risk of developing acute respiratory distress syndrome (ARDS) (39), leading to organ failure, sepsis, or death (40). The pathophysiological mechanisms discussed thus far undoubtedly are just components of a highly complex network of alcohol-induced cellular perturbations.
Chronic Alcohol Intake Compromises Lung Immunity by Altering Immunometabolism in Humans and Mouse Models
- The alcohol-modified ciliary protein blots were probed with phospho-antibodies, and mass spectroscopy was used to detect unique alcohol-driven phosphorylated protein sites.
- Importantly, pneumonia and aspiration events are the most common direct causes of acute lung injury and ARDS (27).
- The over-exuberant response by AMs may have implications for the severity of illness among individuals with pulmonary infections.
- In 1885, Sir William Osler reported that alcohol is one of the greatest predisposing factors to the development of pneumonia (Osler, 1892).
- They observe an alcohol-stimulated release of damaged mitochondrial DNA in cultured alveolar epithelial cells, which could alter phagocytosis in alveolar macrophages.
Therefore, induction of IL-17 cytokine can improve survival of alcohol-treated animals (Ye et al., 2001). Epidemiological studies reveal that oxidative stress is an important risk factor in the etiology of ARDS and COPD (MacNee, 2001; Moss et al., 1996). Often oxidative stress is linked with the oxidation of proteins, lipids and DNA to form oxidized proteins, lipid aldehydes and peroxides such as malondialdehyde (MDA), hexanals and 4-hydroxynenonal (4-HNE), and 8-hydroxy-deoxy-guanosine, which disrupt normal signaling events required for homeostasis and cause cell injury. Therefore, establishing a cause and effect interrelationship between toxicity and oxidative stress by assessing oxidized proteins, lipids or DNA could provide a better understanding of lung injury.
ARDS is a life-threatening form of hypoxemic respiratory failure characterized by inflammation in the lung parenchyma leading to pulmonary edema. Under normal conditions, alveolar epithelial cells form a tight barrier and prevent fluid from traversing the epithelium. In the case of ARDS, the inciting event (e.g., pneumonia) causes lung injury through release of pro-inflammatory cytokines, which result in toxic mediators that damage the pulmonary alveolar epithelium and capillary endothelium. This injury results in leakage of proteinaceous fluid into the normally dry alveolar spaces, causing a significant impairment in gas exchange. Clinically, patients exhibit bilateral pulmonary edema and severe hypoxemia necessitating mechanical ventilation. While alcoholism does not directly cause ARDS, experimental evidence demonstrates that chronic alcohol exposure leaves the alveolar epithelium more leaky and primed for injury.
Alcohol and the Immune System
These expressions can be restored by intrapulmonary administration of recombinant GM-CSF, which improves functional activities of alveolar macrophages in alcohol-fed rats and restores alveolar epithelial barrier function damaged by alcohol ingestion (Pelaez et al., 2004). Recently, we found that primary bronchial smooth muscles cells treated with bronchial lavage fluid from severe asthmatic patients cause ER stress (Kaphalia and Calhoun, 2012). In other study, we found an up-regulation of ATF6 and PERK and/or their downstream signaling in the lungs of hepatic ADH-deficient mice fed ethanol daily for 3 months (kaphalia et al., 2013). In these studies, we found activation of XBP1, protein disulfide isomerase (PDI) and C/EBP homologous protein (CHOP) suggesting a role of ER stress in ethanol-induced lung injury.
Mechanisms of Alcohol-Induced Lung Injury
Pneumoniae in vitro and a complete absence of killing of other bacterial strains in alcohol-exposed animals. In human studies, BACs as low as 0.2 percent (i.e., approximately 2.5 times the legal intoxication level) impaired neutrophil degranulation and bactericidal activity (Tamura et al. 1998). We next investigated the impact of chronic ethanol consumption on the transcriptional landscape of immune cells using scRNA-Seq (Figure 1A). Each cluster was constituted of cells from all subjects, regardless of the time point of collection and SARS-CoV-2 infection (Supp. Fig 2A). The 9 AM clusters were distinct based on several inflammatory and regulatory markers (FABP4, STAT1, CD9.1, MMP10, ISG20, IL1B, CD14, MARCO, LCN2, HYOU1, LYZ, MAMU-DRA) (Supp. Fig 2B). Therefore, a better understanding of the mechanisms by which ethanol and its metabolites regulate the expression and function of transcription factors and inflammatory mediators is needed.
In addition, alcohol consumption can also suppress the recruitment of CD4+ and CD8+ T lymphocytes in response to P. carinii infection in the lungs (Shellito and Olariu, 1998). T cells isolated from chronic alcoholics and ethanol-intoxicated animals possess a decreased response to mitogen stimulation and an impaired hypersensitivity responses (Lundy et al., 1975; Spinozzi et al., 1991). Animal studies of pulmonary tuberculosis have shown decreased lung CD4+ and CD8+ T cells and diminished proliferation in ethanol-fed mice (Mason et al., 2004). In addition to its effects on innate immunity, there are several important consequences of alcohol exposure on adaptive immunity as well. For example, it has been recognized for over a century that alcoholics are at increased risk for infection with Mycobacterium tuberculosis. Active tuberculosis is a unique pulmonary bacterial infection that involves cell-mediated immunity, which is one aspect of the adaptive immune response.
In addition, researchers have identified several regulatory molecules that may play crucial roles in the alcohol-induced disease processes. Although there currently are no approved therapies to combat the detrimental effects of chronic alcohol consumption on the respiratory system, these molecules may be potential therapeutic targets to guide future investigation. Patients with AUDs have enhanced susceptibility to lung injury and respiratory infections, which increase economic costs, morbidity, and alcohols effects on lung health and immunity pmc mortality.
