Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2019 Jun 1.
Published in final edited form as: Alcohol. 2017 Oct 31;69:51–56. doi: 10.1016/j.alcohol.2017.10.006

Summary of the 2017 Alcohol and Immunology Research Interest Group (AIRIG) meeting

Holly J Hulsebus a,b,c, Brenda J Curtis a,b, Patricia E Molina d, Majid Afshar e,f, Lisbeth A Boule a,b, Niya Morris f,g, Ali Keshavarzian h, Jay K Kolls i, Samantha M Yeligar j, Michael E Price k, Todd A Wyatt k, Mashkoor A Choudhry f,g, Elizabeth J Kovacs a,b,c,*
PMCID: PMC5930121  NIHMSID: NIHMS959385  PMID: 29654985

Abstract

On June 24, 2017, the 22nd annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite conference during the annual Research Society on Alcoholism (RSA) Scientific Meeting in Denver, CO. The 2017 meeting focused broadly on mechanisms that link alcohol to tissue injury and inflammation, and how this research can be translated to improve human health. Two plenary sessions comprised the meeting, which first explored the association between alcohol and trauma/tissue injury, and finished with a discussion of alcohol and mucosal inflammation. The presentations encompassed diverse areas of alcohol research, from effects on the brain, to airway and pulmonary systems, to gut barrier disruption. The discussions also thoughtfully highlighted how current laboratory and clinical research can be used to prevent or treat alcohol-related morbidity and mortality.

Keywords: Alcohol, Inflammation, Trauma, Mucosa, Tissue Injury

Introduction

Nearly six percent of all global mortality can be attributed to alcohol use, including 88,000 deaths in the United States, making it the fourth leading cause of preventable death in the U.S. (National Institute on Alcohol Abuse and Alcoholism, 2017). Alcohol misuse contributes to over 200 different diseases and health injuries, including alcohol dependence, liver cirrhosis, and some cancers (World Health Organization, 2014). It has been shown that binge alcohol ingestion can have noticeable pro-inflammatory immune-modulating effects after only 20 minutes (Afshar et al., 2015b), but the mechanisms that contribute to chronic pathologies remain to be fully understood. The focus of the 2017 AIRIG meeting centered on immune pathways and systems involved in tissue and organ dysfunction and the inflammatory response at mucosal sites following alcohol exposure. Specifically, the meeting was divided into two plenary sessions, the first with oral presentations in the area of alcohol and trauma/tissue injury and the second with oral presentations related to alcohol and mucosal inflammation.

Alcohol and Trauma/Tissue Injury

Dr. Elizabeth J. Kovacs, Director of Burn Research and the Alcohol Research Program in the Department of Surgery at the University of Colorado Denver, and Dr. Joe Wang, Program Director for the Division of Metabolism and Health Effects at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), began the 2017 AIRIG meeting with words of welcome and appreciation for the attendees’ dedication to the advancement of alcohol-related immunology research. The welcoming remarks were followed by the first plenary session chaired by Drs. Michael McCaskill (Tulane University) and Philip Roper (Loyola University Chicago), which focused on how alcohol affects tissues and contributes to traumatic injury. Dr. Patricia E. Molina from Louisiana State University Health Sciences Center opened the session with her talk titled “Alcohol-neuroimmune interactions in traumatic brain injury.” Traumatic brain injury (TBI) is a debilitating condition in military and civilian populations (Faul, Wald, & Coronado, 2010; French, 2009), characterized by an early and sharp rise in neuroinflammation followed by a protracted secondary wave of sustained neuroinflammation that is associated with lasting neurological and behavioral deficits that include increased incidence of anxiety and depression, stress, and pain sensitivity, as well as anhedonia and impulse control deficits (Faden, 1993; Riggio, 2011; Werner & Engelhard, 2007). These TBI sequelae promote alcohol abuse in humans through unknown mechanisms (Bombardier, Temkin, Machamer, & Dikmen, 2003; Graham & Cardon, 2008). Because post-TBI alcohol exposure is detrimental to overall recovery through sustained neuroinflammation and excitatory glutamate signaling (Mayeux, Teng, Katz, Gilpin, & Molina, 2015), Dr. Molina’s overall aim is to understand the underlying mechanisms leading to escalation in alcohol drinking post TBI. It has been previously shown that modulation of endocannabinoid tone by systemic administration of JZL184, a monoacylglycerol lipase inhibitor that prevents degradation of the endocannabinoid 2-Arachidonoylglycerol (2-AG), is sufficient to attenuate neuroinflammation and improve neurobehavioral recovery (Katz et al., 2015). Therefore, Dr. Molina’s group tested the hypothesis that post-TBI endocannabinoid degradation inhibition would improve neurobehavioral outcomes, including escalation of alcohol drinking. Adult male Wistar rats were trained to self-administer alcohol in a thirty-minute, free-choice, two-lever fixed ratio (FR1) operant paradigm and subjected to a mild to moderate “single-hit” TBI produced by fluid percussion. The rats were divided into sham TBI+vehicle, or TBI+JZL184 (16 mg/kg intraperitoneally, delivered thirty minutes post TBI), and allowed to self-administer alcohol for two weeks post TBI before sacrifice and brain collection for biochemical analysis. Results showed that a single injection of JZL184 post TBI decreases motivation to drink, attenuates neuroinflammation, rescues dysregulated glutamatergic signaling, and attenuates neuronal hyperexcitability at the site of injury (Mayeux, Katz, Edwards, Middleton, & Molina, 2017). JZL184-administered TBI animals had significantly improved cognitive performance, significantly attenuated pain sensitivity deficits, and significantly attenuated anxiety-like behavior compared to vehicle-injected TBI animals. These data demonstrate that modulation of endocannabinoid tone post TBI has potential therapeutic benefits that persist throughout the acute recovery period (fourteen days post TBI). Dr. Molina’s group speculates that TBI-induced synaptic hyperexcitability at the site of injury may contribute to the development of negative affective behaviors including anxiety-like behavior and escalation of alcohol self-administration post TBI.

Dr. Majid Afshar from Loyola University Chicago presented his work in a talk titled “Alcohol biomarkers to examine organ dysfunction in injured patients.” Alcohol misuse occurs in nearly a quarter of trauma patients, contributes to worsening organ dysfunction, and is associated with deleterious outcomes (Afshar, Netzer, Murthi, & Smith, 2015a; Silver et al., 2008). The dysregulated immune response from alcohol persists even after blood alcohol is no longer detectable in critically ill trauma patients (Chen et al., 2013; Fitzgerald et al., 2007; Li, Kovacs, Schwacha, Chaudry, & Choudhry, 2007). Blood alcohol concentration (BAC) does not characterize the drinking patterns of trauma patients and self-report methods cannot be assessed in patients with severe injury. Therefore, it remains a challenge to identify patients with alcohol misuse in a timely manner so that targeted interventions may be provided. The Alcohol Use Disorders Identification Test (AUDIT) is a self-report tool and the current standard for identifying alcohol misuse in trauma settings (Saunders, Aasland, Babor, de la Fuente, & Grant, 1993). However, severely injured patients may not be capable of providing AUDITs until much later in their care when the institution of timely interventions may have lapsed. In addition, indirect blood biomarkers, like γ-Glutamyltransferase (GGT), Mean Corpuscular Volume (MCV), Carbohydrate Deficient Transferrin (CDT), Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) are confounded by age, gender, organ dysfunction, and nonalcohol-related illnesses and have not proven useful in clinical application (Gough et al., 2015). Direct alcohol biomarkers such as Phosphatidylethanol (PEth) show promise to augment current methods in identifying patients with alcohol misuse (Wurst et al., 2015). PEth homologues are a group of phospholipids formed in the red blood cell membrane in the presence of alcohol by phospholipase D. The advantages of using PEth as an alcohol biomarker are: (1) it has a half-life of 3 to 5 days (detectable up to 28 days), and has demonstrated a dose dependent correlation with single use as well as heavy daily drinking patterns; (2) the sensitivity of PEth has greatly improved with recent development and validation of the liquid chromatography-mass spectrometry assay (Schrock, Thierauf, Wurst, Thon, & Weinmann, 2014); (3) PEth is independent of mental status or recall bias, unlike self-report methods such as the AUDIT; and (4) it is not affected by age, sex, race, comorbidities, and organ dysfunction. Dr. Afshar reported that a cutoff of 250 ng/ml demonstrated good negative and positive predictive values for identifying alcohol misuse in critically-ill patients. Ongoing studies in Dr. Afshar’s laboratory aim to provide additional validation for the clinical application of PEth in the critically-ill, and as a tool to better identify alcohol misuse and patients at-risk for complications and organ dysfunction.

Dr. Lisbeth A. Boule, a post-doctoral fellow in Dr. Elizabeth J. Kovacs’ laboratory at the University of Colorado Denver, presented her work titled “Alcohol intoxication in aged mice alters pulmonary inflammatory responses.” An increasingly common behavior in the elderly is alcohol consumption, as 40% of those >65 years of age drink alcohol (National Institute of Alcohol Abuse and Alcoholism, 2016), and the effects of alcohol ingestion in this population may be more potent in part due to their slowed ability to metabolize alcohol (Kinirons & O’Mahony, 2004; Mangoni & Jackson, 2004; Meier & Seitz, 2008). In addition, the elderly experience a greater prevalence of infection, and increased morbidity and mortality due to infection, which may be attributed to the effects of low-grade chronic inflammation that increases with age (Fung & Monteagudo-Chu, 2010; Van der Horst Graat, Terpstra, Kok, & Schouten, 2007). To test her hypothesis that alcohol consumption will have a more potent negative impact on immunity in older subjects, Dr. Boule used a mouse model of alcohol intoxication and infection. Briefly, young and aged mice were given vehicle or 1 g/kg body weight ethanol via oral gavage, which resulted in a blood alcohol concentration of approximately 100 mg/dL at the time of bacterial infection (30 minutes post ethanol treatment). Dr. Boule showed that intoxicated, aged mice had worse pulmonary pathology 24 hours after infection, including increased cellularity, alveolar wall thickening, and larger inflammatory foci than comparably treated young mice. In parallel experiments, isolated alveolar macrophages from young and aged mice given vehicle or ethanol were stimulated with bacterial products in vitro. After stimulation, alveolar macrophages from young mice given ethanol produced 50% less interleukin (IL) 6 and tumor necrosis factor (TNF) α than those from young mice given vehicle. Additionally, stimulation-induced production of IL-6 by alveolar macrophages was reduced even further (>90%) when macrophages were isolated from aged mice given ethanol. In contrast, ethanol-mediated changes in the production of neutrophil chemoattractants KC (CXCL1 [chemokine (C-X-C motif) ligand 1]) and RANTES (CCL5 [chemokine (C-C motif) ligand 5]) by alveolar macrophages followed a different pattern. Specifically, alveolar macrophages from young mice given ethanol produced less of these chemokines compared to young mice given vehicle control, whereas alveolar macrophages from aged mice given ethanol produced higher levels of both chemokines compared to all other groups of mice. In summary, Dr. Boule showed that aging and ethanol intoxication skew alveolar macrophage function, such that there is decreased production of pro-inflammatory cytokines and increased levels of neutrophil chemoattractants; these consequences likely contribute to the infection-mediated morbidity and mortality observed in aged individuals.

Niya Morris, a Ph.D. student in the laboratory of Dr. Mashkoor A. Choudhry at Loyola University Chicago Health Sciences Division, discussed the role of hypoxia inducible factor 1α (HIF-1α) in impaired microRNA biogenesis in intestinal epithelial cells (IEC) in her talk titled “Role of HIF-1α in gut barrier disruption following ethanol and burn injury.” MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression by binding to the 3′ untranslated region (UTR) sequences of their targets, resulting in messenger RNA (mRNA) degradation or translational repression. To mediate their gene silencing ability, miRs require two maturation steps. Following transcription by RNA polymerase II, the newly formed primary microRNA undergoes nuclear cleavage by Drosha, forming a precursor miRNA (pre-miR). The pre-miR is exported into the cytoplasm where it is cleaved by Dicer prior to formation of the microRNA-induced silencing complex (miRISC) with Argonaute (Finnegan & Pasquinelli, 2013; He & Hannon, 2004). Dysregulation of microRNA biogenesis has been shown to diminish miR expression and impair intestinal barrier function (Gaulke et al., 2014; McKenna et al., 2010). A recent study from the Choudhry laboratory reported that alcohol and burn injury results in a significant reduction in microRNA biogenesis proteins Drosha (52%) and Argonaute-2 (49%), which coincided with reduced miR expression (Morris et al., 2017). Furthermore, the combined insult of alcohol and burn injury results in increased gut leakiness and bacterial translocation one day after injury, possibly due to diminished microRNA biogenesis and miR expression (Rendon, Li, Akhtar, & Choudhry, 2013). Both microRNA expression and biogenesis are negatively impacted by hypoxia (Rupaimoole et al., 2014), which occurs in the intestine as blood flow is redistributed to more vital organs following alcohol and burn injury (Choudhry, Ba, Rana, Bland, & Chaudry, 2005). Similarly, HIF-1α (a marker of hypoxia) is significantly elevated in IECs following alcohol and burn injury. To investigate the role of HIF-1α in microRNA biogenesis following alcohol and burn injury, mice were gavaged with approximately 2.9 g/kg alcohol 4 hours before receiving a 12.5% total body surface area full-thickness burn injury. Immediately following the burn injury, mice received normal saline resuscitation with or without PX-478, an inhibitor of HIF-1α. Ms. Morris’ preliminary findings suggest that treatment of mice with a HIF-1α inhibitor improves microRNA biogenesis following alcohol and burn injury.

Alcohol and Mucosal Inflammation

The second plenary session was chaired by Dr. Marisela Agudelo (Florida International University) and Holly Hulsebus (Ph.D. student in Dr. Elizabeth J. Kovacs’ lab at the University of Colorado Denver); the session began with Dr. Ali Keshavarzian from Rush University Medical Center, who presented his work entitled, “Alcohol-induced gut leakiness to endotoxin and systemic inflammation.” Excessive alcohol consumption can deleteriously impact multiple organs (Wang, Zakhari, & Jung, 2010). However, only a subset of alcoholics develop organ damage such as cirrhosis (Gao & Bataller, 2011), suggesting that excessive alcohol consumption is required but not sufficient for alcoholic organ damage. Multiple studies have demonstrated that inflammation is the required co-factor for alcoholic organ damage (Wang et al., 2010), most likely triggered by alcohol-induced dysbiosis and gut leakiness to endotoxins (Engen, Green, Voigt, Forsyth, & Keshavarzian, 2015). Keshavarzian’s group has shown that alcoholics with liver disease exhibit gut leakiness to endotoxins, while alcoholics without organ damage have normal intestinal permeability (Keshavarzian et al., 1999). His group also showed that a subset of alcoholics had dysbiosis with a decreased abundance of Bacteroidetes and Clostridia, and an increased abundance of pro-inflammatory Proteobacteria (Mutlu et al., 2009). Alcohol disrupts the intestinal barrier through both a direct effect on tight junctional proteins (Elamin, Masclee, Dekker, & Jonkers, 2013) and indirectly through dysbiosis (Llorente & Schnabl, 2015). Keshavarzian’s group and others have shown that alcohol not only impacts microbiota composition (Engen et al., 2015; Mutlu et al., 2009), but also microbiota function, with decreased production of the short chain fatty acid (SCFA) butyrate (Couch et al., 2015). SCFAs are required to maintain intestinal barrier integrity and low levels of butyrate result in disruption of intestinal barrier function (Hamer et al., 2008). Further, several animal studies have provided a causal link between dysbiosis/gut leakiness and organ damage. For example, ameliorating dysbiosis with prebiotics or probiotics prevented alcoholic steatohepatitis (ASH) (Forsyth et al., 2009; Keshavarzian et al., 2001). Further, transplantation of stool from patients with alcoholic hepatitis into alcohol-fed mice caused severe ASH compared to stool transplantation from control subjects (Llopis et al., 2016). Recent data from Keshavarian’s lab suggest that disruption of circadian rhythms promotes alcohol-induced dysbiosis and gut leakiness (Summa et al., 2013; Swanson et al., 2016; Voigt et al., 2014), and could therefore be a susceptibility factor for alcohol-induced, gut-derived inflammation. Disrupted circadian rhythms are common in western societies, affecting at least 30% of the population through shift work and social jet lag (Roenneberg, Allebrandt, Merrow, & Vetter, 2012; Zelinski, Deibel, & McDonald, 2014), which intriguingly correlates to that fact that 30% of alcoholics develop dysbiosis, gut leakiness, and clinically relevant organ damage (Gao & Bataller, 2011). These discoveries will help identify potential novel therapeutic targets to prevent/treat alcohol-associated pathologies.

Dr. Jay K. Kolls from the University of Pittsburgh School of Medicine presented his work in a talk titled “Alcohol and type 17 immunity in the respiratory tract.” Type 17 immunity has been shown to be critical for mucosal protection against extracellular bacteria and fungi, in part by regulating the expression of neutrophil-recruiting chemokines and antimicrobial proteins (Chen et al., 2016; Conti et al., 2016). Using an acute model of ethanol administration in mice, Dr. Kolls’ group has shown a perturbed clearance of Streptococcus pneumoniae in the lung, which was associated with reduced expression of il23a and il17a. Further, they found that IL-17 receptor (IL-17R) signaling regulates the expression of both CXCL1 and CXCL5 in lung epithelium, and reduced levels of these chemokines are observed in acute-ethanol treated mice (Chen et al., 2016). Interestingly, neither recombinant IL-23 nor IL-17 could rescue these mice, suggesting that ethanol also perturbed IL-17R signaling in this model. However, rescue with CXCL1 and to a lesser extent CXCL5, restored bacterial clearance in ethanol-treated mice (Trevejo-Nunez et al., 2015). Taken together, these data suggest that ethanol can inhibit type 17 immune responses but this defect can be overcome by restoring chemokine gradients in lung tissue.

Dr. Samantha M. Yeligar from Emory University/VA Medical Center presented her work titled “Alcohol-induced Nox microRNA down-regulation causes alveolar macrophage phagocytic dysfunction.” Patients with alcohol use disorders (AUDs) are 2-4 times more susceptible to developing respiratory infections than non-alcoholics (Moss et al., 2003). During chronic alcohol consumption, alveolar macrophages exhibit impaired microbial phagocytosis and clearance (Yeligar, Mehta, Harris, Brown, & Hart, 2016). Alcohol-induced alveolar macrophage immune dysfunction is mediated by increases in oxidative stress (Brown, Ping, Harris, & Gauthier, 2007). NADPH oxidases (Nox) 1, 2, and 4 are the primary sources of oxidative stress in the alveolar macrophage. Nox1 and Nox2 primarily produce superoxide, and Nox4 primarily produces hydrogen peroxide (Brown & Griendling, 2009). The experimental models used in Dr. Yeligar’s studies included (a) alveolar macrophages isolated from an in vivo model of chronic alcohol consumption in which male C57BL/6J mice were fed with and without ethanol in their drinking water (20% wt/v) for 12 weeks, and (b) the MH-S mouse alveolar macrophage cell line was treated with and without ethanol (0.08%) for 3 days as an in vitro model of chronic ethanol exposure (Yeligar, Harris, Hart, & Brown, 2012; Yeligar, Harris, Hart, & Brown, 2014; Yeligar et al., 2016). Compared to control, ethanol increased expression of Nox1, Nox2, and Nox4, enhanced oxidative stress as measured by intracellular reactive species production and extracellular hydrogen peroxide generation, and impaired phagocytosis and lysosomal clearance of Staphylococcus aureus bacteria in vivo and in vitro. These ethanol-induced alveolar macrophage derangements were reversed with transfection of silencing RNAs for Nox1, Nox2, and Nox4 or utilization of Nox1 and Nox2 knockout mice (Yeligar et al., 2012). To determine how ethanol increases expression of Nox proteins, miRs that bind to the 3′-UTR of Nox1, Nox2, and Nox4, thereby targeting Nox mRNA for degradation, were investigated. Using in silico analysis, species-conserved binding sites for Nox-related miRs were identified. Ethanol downregulated the expression of Nox1-related miR-1264, Nox2-related miR-107, and Nox4-related miR-92a. MH-S cells transfected with miR-1264 mimic partially reversed ethanol-induced Nox1 and Nox4 mRNA levels, miR-107 mimic transfection partially reversed ethanol-induced Nox2 and Nox4 mRNA levels, and miR-92a mimic transfection completely reversed ethanol-induced Nox4 mRNA levels. Further, ethanol-induced alveolar macrophage oxidative stress and phagocytic dysfunction were mitigated by transfection with Nox-related miR mimics. Taken together, these data suggest that miRs-1264, - 107, and -92a may provide novel therapeutic targets for the treatment of impaired alveolar macrophage immunity and mitigate increased susceptibility to respiratory infections in AUD patients.

The final research presentation was given by Michael E. Price, a Ph.D. student in the laboratory of Joseph H. Sisson at the University of Nebraska Medical Center, titled “Alcohol-driven redox imbalance and mitochondrial dysfunction in ciliated airway epithelial cells.” AUD has long been associated with increased prevalence and worse outcomes of airway disease. Cyclic AMP-dependent protein kinase (PKA) increases in airway ciliary beat frequency are a key defense against inhaled pathogens and debris (Salathe, 2007). Prolonged alcohol exposure causes dysfunctional mucociliary clearance by rendering PKA and ciliary beat frequency desensitized to stimulation (Wyatt, Gentry-Nielsen, Pavlik, & Sisson, 2004). Sisson’s group has previously demonstrated that concomitant feeding of antioxidants to alcohol-drinking mice preserved ciliary beat frequency responsiveness to stimulation (Simet, Pavlik, & Sisson, 2013). In other models of alcohol exposure, mitochondria are an important source of reactive oxygen species (ROS) (Liang, Harris, & Brown, 2014). Thus, Mr. Price hypothesized that alcohol promotes ROS and mitochondrial dysfunction in airway epithelial cells. To test this hypothesis, airway brushings from healthy human non-smoking control subjects (AUDIT < 5; n = 4) and nonsmoking subjects with AUD (AUDIT > 20; n = 6) were sampled from the Colorado Pulmonary Alcohol Research Consortium (CoPARC), and mRNA expression levels of select oxidant related proteins including TrxR1, TrxR2, TXN, XDH, ADH5, GPX2, SOD3, PRXDX1, PRXDX6, GPX3 and NME8, were assessed. To model alcohol exposure in vitro, superoxide dismutase (SOD) 1, SOD2, SOD3, catalase, and mitocatalase were overexpressed in the BEAS-2B cell line (immortalized human bronchial epithelial cells) and then treated with ± 100 mM alcohol for 24 h followed by ± isoproterenol. The outcomes measured included ROS using fluorescent probes mitoSOX and dihydroethidium (DHE) coupled with flow cytometry, mitochondrial function by measuring oxygen consumption rate (OCR) with Seahorse mitostress tests, and PKA activity. In airway brushings from AUD subjects, TrxR1 (p = 0.06) and XDH (p = 0.04) were increased, and SOD3 (p = 0.04) and NME8 (P = 0.08) were decreased compared to control subjects. Alcohol exposure in BEAS-2B cells resulted in increased mitoSOX and DHE detection at baseline compared to control. Interestingly, only mitoSOX was increased with alcohol exposure compared to control. Additionally, alcohol caused a 20% decrease in the maximum OCR and desensitized PKA activity when stimulated with isoproterenol compared to control cells. Importantly, overexpression of SOD1 restored maximum OCR and PKA responsiveness in alcohol-exposed BEAS-2B cells. Mr. Price concluded that alcohol shifts the redox balance in primary human airway epithelial cells to an oxidative phenotype, and alcohol impairs mitochondria function and increases mitochondrial-derived oxidants in BEAS-2B cells. These data implicate the mitochondria as a potentially important source of oxidants to cause PKA and cilia dysfunction.

Summary

The 2017 AIRIG meeting, held during the RSA national conference, showcased research relating to alcohol’s effects on various tissues, organs, and mucosal systems. Several presentations focused on possible therapeutic targets following alcohol-induced morbidity. For example, JZL184, a monoacylglycerol lipase inhibitor, can modulate endocannabinoid tone following traumatic brain injury, HIF-1α inhibition can improve microRNA biogenesis and potentially attenuate gut leakiness following alcohol and burn injury, and fecal transplantation could confer resistance to alcoholic steatohepatitis in alcohol-fed mice. Other presentations focused on alcohol’s effects on the respiratory tract and pulmonary systems. It was shown that aging and ethanol intoxication alter alveolar macrophages to produce less pro-inflammatory cytokines and more neutrophil chemoattractants, and it can also inhibit type 17 immune responses in the lung. Additionally, ethanol increased expression of Nox proteins and enhanced oxidative stress while impairing phagocytosis of bacteria in the lung, and can shift human airway epithelial cells to an oxidative phenotype and impair mitochondrial function. Finally, it was shown that phosphatidylethanol could be used as a potential biomarker for identifying patients with alcohol misuse and determining organ dysfunction. Collectively, these data highlight the varied effects of alcohol on multiple tissue and organ systems – especially mucosal surfaces, and offer many potential pathways to investigate in future alcohol-related studies.

Overview of the 2017 Alcohol and Immunology Research Interest Group (AIRIG) meeting.

Session 1: Alcohol & Trauma/Tissue Injury

  • Patricia E. Molina, M.D., Ph.D., Louisiana State University Health Sciences Center: Alcohol-neuroimmune interactions in traumatic brain injury

  • Majid Afshar, M.D., M.S., Loyola University Chicago Health Sciences Division: Alcohol biomarkers to examine organ dysfunction in injured patients

  • Lisbeth A. Boule, Ph.D., University of Colorado Denver: Alcohol intoxication in aged mice alters pulmonary inflammatory responses

  • Niya Morris, Loyola University Chicago Health Sciences Division: Role of HIF-1α in gut barrier disruption following ethanol and burn injury

Session 2: Alcohol & Mucosal Inflammation

  • Ali Keshavarzian, M.D., Rush University Medical Center: Alcohol-induced gut leakiness to endotoxin and systemic inflammation

  • Jay K. Kolls, M.D., University of Pittsburgh School of Medicine: Alcohol and Type 17 immunity in the respiratory tract

  • Samantha M. Yeligar, Ph.D., Emory University/VA Medical Center: Alcohol-induced Nox microRNA down-regulation causes alveolar macrophage phagocytic dysfunction

  • Michael E. Price, University of Nebraska Medical Center: Alcohol-driven redox imbalance and mitochondrial dysfunction in ciliated airway epithelial cells

Article Highlights.

  • Therapeutic targets for alcohol-induced morbidity

  • Effects of alcohol on alveolar macrophages and airway epithelial cells

  • Potential biomarkers for alcohol misuse and organ dysfunction

Acknowledgments

The authors would like to thank the NIAAA, Loyola University Chicago and University of Colorado Denver’s Alcohol Research Program for financial support for the meeting. Support was also provided by the National Institutes of Health (NIH) under award numbers R13 AA020768 (EJK/MAC), R21 AA023193 (EJK), R01 GM 115257 (EJK), AA023193 (EJK), T32 AA013527 (MAC), R01 AA015731 (MAC), R21 AA022324 (MAC), R00 AA021803 (SMY), F30 AA024676 (MEP), R0 AA008769 (JHS), T32 AA007577 (PEM), AA020216 (AK), AA023417 (AK), R37 HL079142 (JKK), and K23 AA024503 (MA); the Department of Defense under award number W81XWH-11-2-0011 (PEM); and the American Heart Association under award number 13SDG13930003 (SMY). TAW is the recipient of a Research Career Scientist Award (IK6 BX003781) from the Department of Veterans Affairs. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors would like to thank Dr. Ellen Burnham and Jeanette Gaydos from the Colorado Pulmonary Alcohol Research Collaborative (CoPARC), and the Research Symposium on Alcohol for hosting this satellite AIRIG meeting. The authors would also like to thank Renita Alis and Kristin Wojtulewicz at Loyola University Chicago Health Sciences Campus and Elizabeth Vonau from the University of Colorado Denver Anschutz Medical Campus for logistical support.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  1. Afshar M, Netzer G, Murthi S, Smith GS. Alcohol exposure, injury, and death in trauma patients. J Trauma Acute Care Surg. 2015a;79(4):643–648. doi: 10.1097/ta.0000000000000825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Afshar M, Richards S, Mann D, Cross A, Smith GB, Netzer G, Hasday J. Acute immunomodulatory effects of binge alcohol ingestion. Alcohol. 2015b;49(1):57–64. doi: 10.1016/j.alcohol.2014.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bombardier CH, Temkin NR, Machamer J, Dikmen SS. The natural history of drinking and alcohol-related problems after traumatic brain injury. Arch Phys Med Rehabil. 2003;84(2):185–191. doi: 10.1053/apmr.2003.50002. [DOI] [PubMed] [Google Scholar]
  4. Brown DI, Griendling KK. Nox proteins in signal transduction. Free Radic Biol Med. 2009;47(9):1239–1253. doi: 10.1016/j.freeradbiomed.2009.07.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brown LA, Ping XD, Harris FL, Gauthier TW. Glutathione availability modulates alveolar macrophage function in the chronic ethanol-fed rat. Am J Physiol Lung Cell Mol Physiol. 2007;292(4):L824–832. doi: 10.1152/ajplung.00346.2006. [DOI] [PubMed] [Google Scholar]
  6. Chen K, Eddens T, Trevejo-Nunez G, Way EE, Elsegeiny W, Ricks DM, Kolls JK. IL-17 Receptor Signaling in the Lung Epithelium Is Required for Mucosal Chemokine Gradients and Pulmonary Host Defense against K. pneumoniae. Cell Host Microbe. 2016;20(5):596–605. doi: 10.1016/j.chom.2016.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen MM, Bird MD, Zahs A, Deburghgraeve C, Posnik B, Davis CS, Kovacs EJ. Pulmonary inflammation after ethanol exposure and burn injury is attenuated in the absence of IL-6. Alcohol. 2013;47(3):223–229. doi: 10.1016/j.alcohol.2013.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Choudhry MA, Ba ZF, Rana SN, Bland KI, Chaudry IH. Alcohol ingestion before burn injury decreases splanchnic blood flow and oxygen delivery. Am J Physiol Heart Circ Physiol. 2005;288:H716–721. doi: 10.1152/ajpheart.00797.2004. [DOI] [PubMed] [Google Scholar]
  9. Conti HR, Bruno VM, Childs EE, Daugherty S, Hunter JP, Mengesha BG, Gaffen SL. IL-17 Receptor Signaling in Oral Epithelial Cells Is Critical for Protection against Oropharyngeal Candidiasis. Cell Host Microbe. 2016;20(5):606–617. doi: 10.1016/j.chom.2016.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Couch RD, Dailey A, Zaidi F, Navarro K, Forsyth CB, Mutlu E, Keshavarzian A. Alcohol induced alterations to the human fecal VOC metabolome. PLoS One. 2015;10(3):e0119362. doi: 10.1371/journal.pone.0119362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Elamin EE, Masclee AA, Dekker J, Jonkers DM. Ethanol metabolism and its effects on the intestinal epithelial barrier. Nutr Rev. 2013;71(7):483–499. doi: 10.1111/nure.12027. [DOI] [PubMed] [Google Scholar]
  12. Engen PA, Green SJ, Voigt RM, Forsyth CB, Keshavarzian A. The Gastrointestinal Microbiome: Alcohol Effects on the Composition of Intestinal Microbiota. Alcohol Res. 2015;37(2):223–236. doi: 10.35946/arcr.v37.2.07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Faden AI. Experimental neurobiology of central nervous system trauma. Crit Rev Neurobiol. 1993;7(3–4):175–186. [PubMed] [Google Scholar]
  14. Faul M, Wald M, Coronado V. Traumatic brain injury in the United States: Emergency department visits, hospitalizations and deaths 2002–2006. 2010 Retrieved from Atlanta, GA. [Google Scholar]
  15. Finnegan EF, Pasquinelli AE. MicroRNA biogenesis: Regulating the regulators. Critical Reviews in Biochemistry and Molecular Biology. 2013;48:51–68. doi: 10.3109/10409238.2012.738643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fitzgerald DJ, Radek KA, Chaar M, Faunce DE, DiPietro LA, Kovacs EJ. Effects of acute ethanol exposure on the early inflammatory response after excisional injury. Alcohol Clin Exp Res. 2007;31(2):317–323. doi: 10.1111/j.1530-0277.2006.00307.x. [DOI] [PubMed] [Google Scholar]
  17. Forsyth CB, Farhadi A, Jakate SM, Tang Y, Shaikh M, Keshavarzian A. Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis. Alcohol. 2009;43(2):163–172. doi: 10.1016/j.alcohol.2008.12.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. French L. TBI in the military. J Head Trauma Rehabil. 2009;24(1):1–3. doi: 10.1097/HTR.0b013e318197a14c. [DOI] [PubMed] [Google Scholar]
  19. Fung H, Monteagudo-Chu M. Community-acquired pneumonia in the elderly. The American Journal of Geriatric Pharmacotherapy. 2010;8(1):47–62. doi: 10.1016/j.amjopharm.2010.01.003. http://dx.doi.org/10.1016/j.amjopharm.2010.01.003. [DOI] [PubMed] [Google Scholar]
  20. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011;141(5):1572–1585. doi: 10.1053/j.gastro.2011.09.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gaulke CA, Porter M, Han Y, Sankaran-Walters S, Grishina I, George MD, Dandekar S. Intestinal epithelial barrier disruption through altered mucosal microRNA expression in human immunodeficiency virus and simian immunodeficiency virus infections. J Virol. 2014;88:6268–6280. doi: 10.1128/JVI.00097-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gough G, Heathers L, Puckett D, Westerhold C, Ren X, Yu Z, Liangpunsakul S. The Utility of Commonly Used Laboratory Tests to Screen for Excessive Alcohol Use in Clinical Practice. Alcohol Clin Exp Res. 2015;39(8):1493–1500. doi: 10.1111/acer.12780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Graham DP, Cardon AL. An update on substance use and treatment following traumatic brain injury. Ann N Y Acad Sci. 2008;1141:148–162. doi: 10.1196/annals.1441.029. [DOI] [PubMed] [Google Scholar]
  24. Hamer H, Jonkers D, Venema K, Vanhoutvin S, Troost F, Brummer R. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther. 2008;27(2):104–119. doi: 10.1111/j.1365-2036.2007.03562.x. [DOI] [PubMed] [Google Scholar]
  25. He H, Hannon GJ. MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522–531. doi: 10.1038/nrg1379. [DOI] [PubMed] [Google Scholar]
  26. Katz PS, Sulzer JK, Impastato RA, Teng SX, Rogers EK, Molina PE. Endocannabinoid degradation inhibition improves neurobehavioral function, blood-brain barrier integrity, and neuroinflammation following mild traumatic brain injury. J Neurotrauma. 2015;32(5):297–306. doi: 10.1089/neu.2014.3508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Keshavarzian A, Choudhary S, Holmes EW, Yong S, Banan A, Jakate S, Fields JZ. Preventing gut leakiness by oats supplementation ameliorates alcohol-induced liver damage in rats. J Pharmacol Exp Ther. 2001;299(2):442–448. [PubMed] [Google Scholar]
  28. Keshavarzian A, Holmes EW, Patel M, Iber F, Fields JZ, Pethkar S. Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage. Am J Gastroenterol. 1999;94(1):200–207. doi: 10.1111/j.1572-0241.1999.00797.x. [DOI] [PubMed] [Google Scholar]
  29. Kinirons M, O’Mahony M. Drug metabolism and ageing. Br J Clin Pharmacol. 2004;57(5):540–544. doi: 10.1111/j.1365-2125.2004.02096.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Li X, Kovacs EJ, Schwacha MG, Chaudry IH, Choudhry MA. Acute alcohol intoxication increases interleukin-18-mediated neutrophil infiltration and lung inflammation following burn injury in rats. Am J Physiol Lung Cell Mol Physiol. 2007;292(5):L1193–1201. doi: 10.1152/ajplung.00408.2006. [DOI] [PubMed] [Google Scholar]
  31. Liang Y, Harris F, Brown L. Alcohol induced mitochondrial oxidative stress and alveolar macrophage dysfunction. Biomed Res Int. 2014;37(1):593. doi: 10.1155/2014/371593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Llopis M, Cassard AM, Wrzosek L, Boschat L, Bruneau A, Ferrere G, Perlemuter G. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut. 2016;65(5):830–839. doi: 10.1136/gutjnl-2015-310585. [DOI] [PubMed] [Google Scholar]
  33. Llorente C, Schnabl B. The Gut Microbiota and Liver Disease. Cell Mol Gastroenterol Hepatol. 2015;1(3):275–284. doi: 10.1016/j.jcmgh.2015.04.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Mangoni A, Jackson S. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. 2004;57(1):6–14. doi: 10.1046/j.1365-2125.2003.02007.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mayeux J, Katz P, Edwards S, Middleton J, Molina P. Inhibition of Endocannabinoid Degradation Improves Outcomes from Mild Traumatic Brain Injury: A Mechanistic Role for Synaptic Hyperexcitability. J Neurotrauma. 2017;34(2):436–443. doi: 10.1089/neu.2016.4452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mayeux J, Teng S, Katz P, Gilpin N, Molina P. Traumatic brain injury induces neuroinflammation and neuronal degeneration that is associated with escalated alcohol self-administration in rats. Behav Brain Res. 2015;279:22–30. doi: 10.1016/j.bbr.2014.10.053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. McKenna LB, Schug J, Vourekas A, McKenna JB, Friedman JR, Kaestner KH. MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function. Gasteroenterology. 2010;139:1654–1664. doi: 10.1053/j.gastro.2010.07.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Meier P, Seitz HK. Age, alcohol metabolism and liver disease. Curr Opin Clin Nutr Metab Care. 2008;11(1):21–26. doi: 10.1097/MCO.0b013e3282f30564. [DOI] [PubMed] [Google Scholar]
  39. Morris NL, Hammer AM, Cannon AR, Gagnon RC, Li X, Choudhry MA. Dysregulation of microRNA biogenesis in the small intestine after ethanol and burn injury. Biochim Biophys Act. 2017 doi: 10.1016/j.bbadis.2017.03.025. In press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Moss M, Parsons PE, Steinberg KP, Hudson LD, Guidot DM, Burnham EL, Cotsonis GA. Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock. Crit Care Med. 2003;31(3):869–877. doi: 10.1097/01.ccm.0000055389.64497.11. [DOI] [PubMed] [Google Scholar]
  41. Mutlu E, Keshavarzian A, Engen P, Forsyth CB, Sikaroodi M, Gillevet P. Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats. Alcohol Clin Exp Res. 2009;33(10):1836–1846. doi: 10.1111/j.1530-0277.2009.01022.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. National Institute of Alcohol Abuse and Alcoholism. Alcohol & Your Health: Older Adults. 2016 Retrieved from https://www.niaaa.nih.gov/alcohol-health/special-populations-co-occurring-disorders/older-adults.
  43. National Institute on Alcohol Abuse and Alcoholism. Alcohol facts and statistics. 2017 Retrieved from https://pubs.niaaa.nih.gov/publications/AlcoholFacts&Stats/AlcoholFacts&Stats.htm.
  44. Rendon JL, Li X, Akhtar S, Choudhry MA. Interleukin-22 modulates gut epithelial and immune barrier functions following acute alcohol exposure and burn injury. Shock. 2013;39:11–18. doi: 10.1097/SHK.0b013e3182749f96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Riggio S. Traumatic brain injury and its neurobehavioral sequelae. Neurol Clin. 2011;29(1):35–47. vii. doi: 10.1016/j.ncl.2010.10.008. [DOI] [PubMed] [Google Scholar]
  46. Roenneberg T, Allebrandt KV, Merrow M, Vetter C. Social jetlag and obesity. Curr Biol. 2012;22(10):939–943. doi: 10.1016/j.cub.2012.03.038. [DOI] [PubMed] [Google Scholar]
  47. Rupaimoole R, Wu SY, Pradeep S, Ivan C, Pecot CV, Gharpure KM, Sood AK. Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression. Nat Comm. 2014;5:5202. doi: 10.1038/ncomms6202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Salathe M. Regulation of mammalian ciliary beating. Annu Rev Physiol. 2007;69:401–422. doi: 10.1146/annurev.physiol.69.040705.141253. [DOI] [PubMed] [Google Scholar]
  49. Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption–II. Addiction. 1993;88(6):791–804. doi: 10.1111/j.1360-0443.1993.tb02093.x. [DOI] [PubMed] [Google Scholar]
  50. Schrock A, Thierauf A, Wurst FM, Thon N, Weinmann W. Progress in monitoring alcohol consumption and alcohol abuse by phosphatidylethanol. Bioanalysis. 2014;6(17):2285–2294. doi: 10.4155/bio.14.195. [DOI] [PubMed] [Google Scholar]
  51. Silver GM, Albright JM, Schermer CR, Halerz M, Conrad P, Ackerman PD, Gamelli RL. Adverse clinical outcomes associated with elevated blood alcohol levels at the time of burn injury. J Burn Care Res. 2008;29(5):784–789. doi: 10.1097/BCR.0b013e31818481bc. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Simet S, Pavlik J, Sisson J. Dietary antioxidants prevent alcohol-induced ciliary dysfunction. Alcohol. 2013;47(8):629–635. doi: 10.1016/j.alcohol.2013.09.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Summa KC, Voigt RM, Forsyth CB, Shaikh M, Cavanaugh K, Tang Y, Keshavarzian A. Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Hepatic Pathology and Inflammation. PLoS One. 2013;8(6):e67102. doi: 10.1371/journal.pone.0067102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Swanson GR, Gorenz A, Shaikh M, Desai V, Kaminsky T, Van Den Berg J, Keshavarzian A. Night workers with circadian misalignment are susceptible to alcohol-induced intestinal hyperpermeability with social drinking. Am J Physiol Gastrointest Liver Physiol. 2016;311(1):G192–201. doi: 10.1152/ajpgi.00087.2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Trevejo-Nunez G, Chen K, Dufour JP, Bagby GJ, Horne WT, Nelson S, Kolls JK. Ethanol impairs mucosal immunity against Streptococcus pneumoniae infection by disrupting interleukin 17 gene expression. Infect Immun. 2015;83(5):2082–2088. doi: 10.1128/iai.02869-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Van der Horst Graat JM, Terpstra JS, Kok FJ, Schouten EG. Alcohol, smoking, and physical activity related to respiratory infections in elderly people. J Nutr Health Aging. 2007;11(1):80–85. [PubMed] [Google Scholar]
  57. Voigt RM, Forsyth CB, Green SJ, Mutlu E, Engen P, Vitaterna MH, Keshavarzian A. Circadian disorganization alters intestinal microbiota. PLoS One. 2014;9(5):e97500. doi: 10.1371/journal.pone.0097500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wang HJ, Zakhari S, Jung MK. Alcohol, inflammation, and gut-liver-brain interactions in tissue damage and disease development. World J Gastroenterol. 2010;16(11):1304–1313. doi: 10.3748/wjg.v16.i11.1304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth. 2007;99(1):4–9. doi: 10.1093/bja/aem131. [DOI] [PubMed] [Google Scholar]
  60. World Health Organization. global status report on alcohol and health - 2014. 2014 Retrieved from http://www.who.int/substance_abuse/publications/global_alcohol_report/msb_gsr_2014_1.pdf?ua=1.
  61. Wurst FM, Thon N, Yegles M, Schruck A, Preuss UW, Weinmann W. Ethanol metabolites: their role in the assessment of alcohol intake. Alcohol Clin Exp Res. 2015;39(11):2060–2072. doi: 10.1111/acer.12851. [DOI] [PubMed] [Google Scholar]
  62. Wyatt T, Gentry-Nielsen M, Pavlik J, Sisson J. Densitization of PKA-stimulated ciliary dysfunction in an ethanol-fed rat model of cigarette smoke exposure. Alcohol Clin Exp Res. 2004;28(7):998–1004. doi: 10.1097/01.ALC.0000130805.75641.F4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Yeligar SM, Harris FL, Hart CM, Brown LA. Ethanol induces oxidative stress in alveolar macrophages via upregulation of NADPH oxidases. J Immunol. 2012;188(8):3648–3657. doi: 10.4049/jimmunol.1101278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Yeligar SM, Harris FL, Hart CM, Brown LA. Glutathione attenuates ethanol-induced alveolar macrophage oxidative stress and dysfunction by downregulating NADPH oxidases. Am J Physiol Lung Cell Mol Physiol. 2014;306(5):L429–441. doi: 10.1152/ajplung.00159.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Yeligar SM, Mehta AJ, Harris FL, Brown LA, Hart CM. Peroxisome Proliferator-Activated Receptor gamma Regulates Chronic Alcohol-Induced Alveolar Macrophage Dysfunction. Am J Respir Cell Mol Biol. 2016;55(1):35–46. doi: 10.1165/rcmb.2015-0077OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Zelinski EL, Deibel SH, McDonald RJ. The trouble with circadian clock dysfunction: multiple deleterious effects on the brain and body. Neurosci Biobehav Rev. 2014;40:80–101. doi: 10.1016/j.neubiorev.2014.01.007. [DOI] [PubMed] [Google Scholar]

RESOURCES