• Alcohol
• Comorbidities
• Exosomes
• Exposome
• Exposomics
• Extracellular Vesicles

• Humans
• Exposome
• Ethanol/adverse effects
• Alcohol Drinking/adverse effects
• Environmental Exposure/adverse effects

• I01 BX005886 BLRD VA
• IK6 BX005962 BLRD VA
• P50 AA030407 NIAAA NIH HHS
• U54 OH010162 NIOSH CDC HHS

• Iron
• copper
• inflammation
• lung
• oxidative damage
• zinc

• Humans
• Pulmonary Disease, Chronic Obstructive
• Copper/therapeutic use
• Lung
• Oxidative Stress
• Iron/therapeutic use
• Zinc/therapeutic use

• Causal relationship
• Dietary intake
• Idiopathic pulmonary fibrosis
• Mendelian randomization
• Prevention strategy

• Diet
• Eating
• Fruit
• Genome-Wide Association Study
• Idiopathic Pulmonary Fibrosis/genetics
• Mendelian Randomization Analysis
• Vegetables
• Humans

• 2020-PT320-005 NHC Key Laboratory of Pneumoconiosis in Shanxi

• GM-CSF
• TGFβ1
• alcohol
• co-culture
• epithelial barrier function

• T32 HL116271 NHLBI NIH HHS
• R03 AA027662-01A1 NIAAA NIH HHS
• R01 AA029690 NIAAA NIH HHS
• R01 AA025857 NIAAA NIH HHS
• R01 AA025854 NIAAA NIH HHS

• Sickle cell disease
• acute chest syndrome
• alveolar type 2 epithelial cells
• inflammation
• lung alveolar macrophages
• surfactant proteins

• Mice
• Humans
• Animals
• Macrophages, Alveolar/metabolism
• Macrophages, Alveolar/pathology
• Endothelial Cells/metabolism
• Leukocytes, Mononuclear/metabolism
• Lung/pathology
• Cytokines/metabolism
• Anemia, Sickle Cell/pathology
• Surface-Active Agents/metabolism
• Mice, Inbred C57BL

• L60 MD013112 NIMHD NIH HHS
• R01 HL138423 NHLBI NIH HHS
• U01 HL117721 NHLBI NIH HHS
• National Institutes of Health and National Heart Lung and Blood Institute

• Humans
• Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
• Lung/metabolism
• Lung Diseases, Interstitial
• Macrophages, Alveolar
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism

• alcohol
• brush border membrane
• ethanol
• intestine
• nutrient absorption

• Alcohol use
• Causal relationship
• Infectious disease
• Mendelian randomization
• Tobacco

• brain
• brain injury
• neurotoxicity
• stroke
• zinc

• Humans
• Infant, Newborn
• Zinc/metabolism
• Central Nervous System/metabolism
• Brain/metabolism
• Metals/metabolism
• Neurodegenerative Diseases/metabolism

• 82071331 National Natural Science Foundation of China
• 2018YFC1312200 National Key Research and Development Program of China
• 81870942 National Natural Science Foundation of China

• Barrier function
• Lung epithelium
• Tight junction
• Toll-like receptor-4.

• Humans
• Tight Junctions/metabolism
• Toll-Like Receptor 4/metabolism
• Lung Injury/pathology
• Epithelial Cells/metabolism
• Epithelium/metabolism

• R01 HL136325 NHLBI NIH HHS
• Careers in Immunology Fellowship Application #13916 American Association of Immunologists
• R01 HL136325 NHLBI NIH HHS

• alcohol
• alcohol use disorder (AUD)
• alveolar macrophage (AM)
• innate immunity
• oxidative stress
• tuberculosis

The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care—but also medical prophylactic and therapeutic care in general—to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.

• COVID
• Vitamin A
• Vitamin D
• barrier function
• claudin
• critical care
• inflammation
• micronutrient
• sepsis
• tight junction
• virus
• zinc

• Apoptosis
• COPD
• cigarette smoke
• efferocytosis
• inflammation
• necrosis
• neutrophil

Electronic cigarettes (ECs) are a modern nicotine delivery system that rapidly grew in widespread use, particularly in younger populations. Given the long history of the comorbidity of alcohol and nicotine use, the rising prevalence of ECs raises the question as to their role in the consumption of alcohol. Of the numerous models of ECs available, JUUL is the most popular. This narrative review aims to determine current trends in literature regarding the relationship between EC and alcohol dual use, as well as hypothesize potential pathogenic tissue damage and summarize areas for future study, including second-hand vapor exposure and calling for standardization among studies. In summary, EC users are more likely to participate in hazardous drinking and are at higher risk for alcohol use disorder (AUD). We surmise the pathogenic damage of dual use may exhibit an additive effect, particularly in pathogen clearance from the lungs, increased inflammation and decreased immune response, physical damage to epithelial cells, and exacerbation of chronic obstructive pulmonary disease (COPD)-like illnesses. A better understanding of pathogenic damages is critical to understand the risks placed on dual users when exposed to respiratory pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

• alcohol misuse
• eCIG
• ethanol
• polysubstance use
• vaping

• bacterial infection
• cytokine biology
• innate immunity
• neutrophil biology
• respiratory infection

• Alcohol abuse
• Alcoholism
• Catalase
• GSH
• MDA
• SOD
• Trace elements

• Adult
• Alcoholism/blood
• Antioxidants/metabolism
• Catalase/blood
• Glutathione/blood
• Humans
• Male
• Middle Aged
• Oxidants/blood
• Superoxide Dismutase/blood
• Trace Elements/blood

• Alveolar macrophage
• Fetal ethanol exposure
• Phagocytic function
• Zinc insufficiency
• Zinc transporters

• Acute respiratory distress syndrome
• Alcohol use disorder
• GM-CSF
• Metabolism
• Pneumonia
• Pulmonary surfactant

• Alcoholism/complications
• Alcoholism/pathology
• Animals
• Granulocyte-Macrophage Colony-Stimulating Factor/deficiency
• Homeostasis
• Lung/drug effects
• Lung/pathology
• Macrophages, Alveolar/pathology
• Pulmonary Alveolar Proteinosis/etiology
• Pulmonary Alveolar Proteinosis/pathology
• Pulmonary Surfactants/metabolism

• R21 AA023571 NIAAA NIH HHS
• T32 AA007463 NIAAA NIH HHS

Antiretroviral therapy extends survival but does not eliminate HIV from its cellular reservoirs. Between immune and stromal cells in the tissue microenvironment, a dynamic intercellular communication might influence host viral immune responses via intercellular transfer of extracellular vehicles (EVs) (microvesicles, exosome, or apoptotic bodies). It is increasingly recognized that HIV-infected macrophage-secreted nucleotide-rich exosomes might play a critical role in mediating communication between macrophages and other structural cells; however, molecular mechanisms underlying cell–cell crosstalk remain unknown. Here we show that HIV-1-infected macrophages and HIV-1 proteins Tat or gp120-treated macrophages express high levels of microRNAs, including miR-23a and miR-27a. Identical miRNAs expression patterns were detected in macrophage-secreted exosomes isolated from bronchoalveolar lavage fluid of HIV transgenic rats. Tat-treated macrophage-derived exosomal miR-23a attenuated posttranscriptional modulation of key tight junction protein zonula occludens (ZO-1) 3′-UTR in epithelial cells. In parallel, exosomal miR-27a released from Tat-treated macrophages altered the mitochondrial bioenergetics of recipient lung epithelial cells by targeting peroxisome proliferator-activated receptor gamma (PPARγ), while simultaneously stimulating glycolysis. Together, exosomal miRNAs shuttle from macrophages to epithelial cells and thereby explain in part HIV-mediated lung epithelial barrier dysfunction. These studies suggest that targeting miRNAs may be of therapeutic value to enhance lung health in HIV.

• cardiovascular disease
• metallothionein
• nitric oxide
• vasculature
• zinc transporters

• ARDS
• alcohol consumption
• meta-analysis
• systematic review

• Alcohol Drinking/adverse effects
• Global Health
• Humans
• Morbidity/trends
• Respiratory Distress Syndrome/epidemiology
• Respiratory Distress Syndrome/etiology

• MR/K023195/1 Medical Research Council

• Endotoxemia
• Ethanol
• Gut permeability
• Inflammation
• Zinc

• anti-ricin small molecules
• antitoxins
• countermeasures
• disease-modifying agents
• pulmonary intoxication
• ricin

• Animals
• Antitoxins/therapeutic use
• Humans
• Lung Diseases/chemically induced
• Lung Diseases/drug therapy
• Ricin/toxicity

Alcohol use disorders are common both in the United States and globally, and are associated with a variety of co-morbid, inflammation-linked diseases. The pathogenesis of many of these ailments are driven by the activation of the NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the pro-inflammatory cytokines IL-1β and IL-18. We hypothesized that protracted exposure of leukocytes to ethanol would amplify inflammasome activation, which would help to implicate mechanisms involved in diseases associated with both alcoholism and aberrant NLRP3 inflammasome activation. Here we show that long-term ethanol exposure of human peripheral blood mononuclear cells and a mouse macrophage cell line (J774) amplifies IL-1β secretion following stimulation with NLRP3 agonists, but not with AIM2 or NLRP1b agonists. The augmented NRLP3 activation was mediated by increases in iNOS expression and NO production, in conjunction with increases in mitochondrial membrane depolarization, oxygen consumption rate, and ROS generation in J774 cells chronically exposed to ethanol (CE cells), effects that could be inhibited by the iNOS inhibitor SEITU, the NO scavenger carboxy-PTIO, and the mitochondrial ROS scavenger MitoQ. Chronic ethanol exposure did not alter K⁺ efflux or Zn²⁺ homeostasis in CE cells, although it did result in a lower intracellular concentration of NAD⁺. Prolonged administration of acetaldehyde, the product of alcohol dehydrogenase (ADH) mediated metabolism of ethanol, mimicked chronic ethanol exposure, whereas ADH inhibition prevented ethanol-induced IL-1β hypersecretion. Together, these results indicate that increases in iNOS and mitochondrial ROS production are critical for chronic ethanol-induced IL-1β hypersecretion, and that protracted exposure to the products of ethanol metabolism are probable mediators of NLRP3 inflammasome hyperactivation.

•

Chronic ethanol exposure amplifies NLRP3 inflammasome-induced IL-1β secretion.

• Ethanol
• IL-1β
• Inflammasome
• Inflammation

• alcohol consumption
• alcohol use disorder
• alcoholic lung
• lung
• lung disease
• lung injury
• respiratory system
• pulmonary system
• alveolar macrophage
• antioxidant

• Alcohol-Related Disorders/complications
• Animals
• Humans
• Lung Diseases/drug therapy
• Lung Diseases/etiology
• Lung Diseases/metabolism

• IK2 CX000643 CSRD VA
• R01 AA017627 NIAAA NIH HHS
• R01 HL125042 NHLBI NIH HHS

• Cytokines
• Hepatic protein synthesis
• Inflammatory response
• Sepsis
• Zinc deficiency

• Airway cilia
• Alcohol
• Alveolar macrophage
• Gut-liver-lung axis
• Lung immunity
• Lung injury

• Alcohol Drinking/adverse effects
• Alcohol Drinking/immunology
• Animals
• Ethanol/administration & dosage
• Ethanol/toxicity
• Gastrointestinal Tract/drug effects
• Gastrointestinal Tract/immunology
• Humans
• Immunity, Cellular/drug effects
• Immunity, Cellular/immunology
• Lung Injury/chemically induced
• Lung Injury/immunology
• Macrophages, Alveolar/drug effects
• Macrophages, Alveolar/immunology
• Oxidative Stress/drug effects
• Oxidative Stress/immunology

• R01 AA012197 NIAAA NIH HHS
• F30 AA024676 NIAAA NIH HHS
• R01 AA008769 NIAAA NIH HHS
• T32 AA013527 NIAAA NIH HHS
• P50 AA013757 NIAAA NIH HHS
• R00 AA021803 NIAAA NIH HHS
• F30 AA022856 NIAAA NIH HHS
• R01 AA012034 NIAAA NIH HHS
• R01 GM115257 NIGMS NIH HHS
• K99 AA021803 NIAAA NIH HHS
• R24 AA019661 NIAAA NIH HHS
• UL1 TR001082 NCATS NIH HHS
• F32 AA019859 NIAAA NIH HHS
• R21 AA023193 NIAAA NIH HHS

Alcohol is the most commonly used and abused drug in the world, and alcohol use disorders pose a tremendous burden to healthcare systems around the world. The lifetime prevalence of alcohol abuse in the United States is estimated to be around 18%, and the economic consequences of these disorders are staggering. Studies on hospitalized patients demonstrate that about one in four patients admitted to critical care units will have alcohol-related issues, and unhealthy alcohol consumption is responsible for numerous clinical problems encountered in intensive care unit (ICU) settings. Patients with alcohol use disorders are not only predisposed to developing withdrawal syndromes and other conditions that often require intensive care, they also experience a considerably higher rate of complications, longer ICU and hospital length of stay, greater resource utilization, and significantly increased mortality compared to similar critically ill patients who do not abuse alcohol. Specific disorders seen in the critical care setting that are impacted by alcohol abuse include delirium, pneumonia, acute respiratory distress syndrome, sepsis, gastrointestinal hemorrhage, trauma, and burn injuries. Despite the substantial burden of alcohol-induced disease in these settings, critical care providers often fail to identify individuals with alcohol use disorders, which can have significant implications for this vulnerable population and delay important clinical interventions.

• Alcoholism
• Alcohol withdrawal delirium
• Alcohol-related disorders critical illness
• Intensive care
• Pneumonia
• Sepsis
• Acute respiratory distress syndrome
• Delirium
• Trauma

• IK2 CX000643 CSRD VA

Ethanol (EtOH) is the world’s most commonly used drug, and has been widely recognized as a risk factor for developing lung disorders. Chronic EtOH exposure affects all of the organ systems in the body and increases the risk of developing pulmonary diseases such as acute lung injury and pneumonia, while exacerbating the symptoms and resulting in increased mortality in many other lung disorders. EtOH and its metabolites inhibit the immune response of alveolar macrophages (AMs), increase airway leakage, produce damaging reactive oxygen species (ROS), and disrupt the balance of antioxidants/oxidants within the lungs. In this article, we review the role of EtOH exposure in the pathogenesis and progression of pulmonary disease.

• COPD
• dysfunction
• ethanol
• lung
• pneumonia

• Alcoholism/complications
• Animals
• Ethanol/toxicity
• Extracellular Matrix/drug effects
• Humans
• Lung/drug effects
• Lung/immunology
• Lung/metabolism
• Lung Diseases/etiology
• Lung Diseases/immunology
• Lung Diseases/metabolism

• K01 HL084684 NHLBI NIH HHS
• K01HL084684 NHLBI NIH HHS

Both Alcoholic Liver Disease (ALD) and alcohol-related susceptibility to acute lung injury are estimated to account for the highest morbidity and mortality related to chronic alcohol abuse and, thus, represent a focus of intense investigation. In general, alcohol-induced derangements to both organs are considered to be independent and are often evaluated separately. However, the liver and lung share many general responses to damage, and specific responses to alcohol exposure. For example, both organs possess resident macrophages that play key roles in mediating the immune/inflammatory response. Additionally, alcohol-induced damage to both organs appears to involve oxidative stress that favors tissue injury. Another mechanism that appears to be shared between the organs is that inflammatory injury to both organs is enhanced by alcohol exposure. Lastly, altered extracellular matrix (ECM) deposition appears to be a key step in disease progression in both organs. Indeed, recent studies suggest that early subtle changes in the ECM may predispose the target organ to an inflammatory insult. The purpose of this chapter is to review the parallel mechanisms of liver and lung injury in response to alcohol consumption. This chapter will also explore the potential that these mechanisms are interdependent, as part of a gut-liver-lung axis.

• ethanol
• extracellular matrix
• hepatic
• inflammation
• pulmonary

• Ethanol
• Molecular mechanisms
• Oro-esophageal squamous cell carcinoma

• Alcohol Drinking/adverse effects
• Alcohol Drinking/metabolism
• Carcinoma, Squamous Cell/etiology
• Carcinoma, Squamous Cell/metabolism
• Esophageal Neoplasms/etiology
• Esophageal Neoplasms/metabolism
• Esophageal Squamous Cell Carcinoma
• Ethanol/poisoning
• Humans
• Signal Transduction

• U54 AA019765 NIAAA NIH HHS
• U54 AA019767 NIAAA NIH HHS

• ARDS, Acute Respiratory Distress Syndrome
• GM-CSF, Granulocyte Macrophage Colony Stimulating Factor
• IL, interleukin
• IκB, Inhibitor of κB
• JAM-A, junctional adhesion molecule A
• LPS, lipolysaccharide
• NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
• PBS, phosphate buffered saline
• TER, transepithelial resistance
• TNF, Tumor Necrosis Factor
• ZO, zonula occludens
• alveolus
• claudin
• lung barrier
• tight junction

• alcohol use
• alcohol use and misuse
• alcoholism
• alcoholics
• infection
• immunity
• immune system
• pneumonia
• molecular mechanisms
• secondary immune deficiency
• gut
• lower respiratory mucosal immunity

• alcohol use, abuse, and dependence
• alcohol use disorder
• immunity
• impaired immune response
• innate immune response
• lung disorders
• pneumonia
• tuberculosis
• respiratory syncytial virus infection
• acute respiratory distress syndrome
• pulmonary infection
• neutrophils, lymphocytes, alveolar macrophages
• pathophysiology

• Animals
• Carrier Proteins/analysis
• Carrier Proteins/biosynthesis
• Ethanol/adverse effects
• Female
• Macrophages, Alveolar/chemistry
• Macrophages, Alveolar/drug effects
• Macrophages, Alveolar/physiology
• Mice
• Mice, Inbred C57BL
• Phagocytosis/drug effects
• Pregnancy
• Pregnancy Complications/chemically induced
• Zinc/analysis
• Zinc/deficiency

• R21 HD078121 NICHD NIH HHS
• 1 P50 AA135757 NIAAA NIH HHS
• 5R01 012197 PHS HHS

Our previous studies have shown that nutritional zinc restriction exacerbates airway inflammation accompanied by an increase in caspase-3 activation and an accumulation of apoptotic epithelial cells in the bronchioles of the mice. Normally, apoptotic cells are rapidly cleared by macrophage efferocytosis, limiting any secondary necrosis and inflammation. We therefore hypothesized that zinc deficiency is not only pro-apoptotic but also impairs macrophage efferocytosis. Impaired efferocytic clearance of apoptotic epithelial cells by alveolar macrophages occurs in chronic obstructive pulmonary disease (COPD), cigarette-smoking and other lung inflammatory diseases. We now show that zinc is a factor in impaired macrophage efferocytosis in COPD. Concentrations of zinc were significantly reduced in the supernatant of bronchoalveolar lavage fluid of patients with COPD who were current smokers, compared to healthy controls, smokers or COPD patients not actively smoking. Lavage zinc was positively correlated with AM efferocytosis and there was decreased efferocytosis in macrophages depleted of Zn in vitro by treatment with the membrane-permeable zinc chelator TPEN. Organ and cell Zn homeostasis are mediated by two families of membrane ZIP and ZnT proteins. Macrophages of mice null for ZIP1 had significantly lower intracellular zinc and efferocytosis capability, suggesting ZIP1 may play an important role. We investigated further using the human THP-1 derived macrophage cell line, with and without zinc chelation by TPEN to mimic zinc deficiency. There was no change in ZIP1 mRNA levels by TPEN but a significant 3-fold increase in expression of another influx transporter ZIP2, consistent with a role for ZIP2 in maintaining macrophage Zn levels. Both ZIP1 and ZIP2 proteins were localized to the plasma membrane and cytoplasm in normal human lung alveolar macrophages. We propose that zinc homeostasis in macrophages involves the coordinated action of ZIP1 and ZIP2 transporters responding differently to zinc deficiency signals and that these play important roles in macrophage efferocytosis.

• Animals
• Bronchoalveolar Lavage Fluid
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Cation Transport Proteins/genetics
• Cation Transport Proteins/metabolism
• Cell Line
• Cytosol/metabolism
• Disease Models, Animal
• Ethylenediamines/pharmacology
• Female
• Gene Expression
• Humans
• Macrophages/immunology
• Macrophages/metabolism
• Macrophages, Alveolar/immunology
• Macrophages, Alveolar/metabolism
• Mice
• Mice, Knockout
• Phagocytosis/immunology
• Pulmonary Disease, Chronic Obstructive/genetics
• Pulmonary Disease, Chronic Obstructive/immunology
• Pulmonary Disease, Chronic Obstructive/metabolism
• Zinc/metabolism

Increasing evidence from human and laboratory studies showed the effect of zinc (Zn) on diabetic complications. Nuclear factor-erythroid 2-related factor 2 (Nrf2) plays important role in the prevention of oxidative damage. This study was to define whether Zn statues (deficiency or supplement) affect the Nrf2 expression and function, and also affect the damage severity of human renal tubular (HK11) cells exposed to high glucose (HG) with palmitate (Pal) and kidney of diabetic mice induced by multiple low-dose streptozotocins. For Zn deficiency diabetic mice were treated with Zn chelator PTEN at 5 mg/kg bw daily for 4 months. Results showed that HG/Pal significantly increased the expression of pro-fibrotic mediators, connective tissue growth factor and PAI-1, in HK11 cells, which was exacerbated by TPEN that depleted intracellular free Zn and decreased Nrf2 expression and transcription. Zn supplement prevented the effects of TPEN and also increased Akt and GSK-3β phosphorylation with a decrease in Nrf2 nuclear exporter, Fyn. All these effects of Zn were abolished by Akt inhibitor. Therefore, Zn up-regulates Nrf2 function via activating Akt-mediated inhibition of Fyn function. Treatment of diabetic mice with TPEN decreased renal Zn level and Nrf2 expression and transcription, with an exacerbation of renal oxidative damage, inflammation and fibrosis. These results suggest the essentiality of Zn for Nrf2 expression and transcription function.

• Akt phosphorylation
• Fyn
• Nrf2
• TPEN
• diabetic nephropathy
• zinc chelation

• Alcohol
• Hemorheology
• Liver injury
• Oxidative stress
• Zn(II)–curcumin

• Alcoholism/blood
• Alcoholism/drug therapy
• Alcoholism/metabolism
• Alcoholism/pathology
• Animals
• Blood Viscosity/drug effects
• Curcumin/chemistry
• Curcumin/pharmacology
• Curcumin/therapeutic use
• Disease Models, Animal
• Erythrocyte Aggregation/drug effects
• Ethanol
• Female
• Glutathione/metabolism
• Hematocrit
• Liver/drug effects
• Liver/pathology
• Malondialdehyde/blood
• Oxidative Stress/drug effects
• Protective Agents/pharmacology
• Protective Agents/therapeutic use
• Rats, Sprague-Dawley
• Superoxide Dismutase/metabolism
• Zinc/chemistry
• Zinc/pharmacology
• Zinc/therapeutic use
• gamma-Glutamyltransferase/blood

Despite antiretroviral therapy, lung disease is a leading cause of death in individuals infected with human immunodeficiency virus type 1 (HIV). Individuals infected with HIV are susceptible to serious bacterial and viral infections, such as pneumococcus and influenza, which are particularly problematic for lung health, resulting in lung injury. Additionally, HIV-infected individuals are susceptible to a number of pulmonary diseases for unknown reasons. Alcohol, the most commonly abused drug in the world, continues to exact an enormous toll on morbidity and mortality in individuals living with HIV. Chronic alcohol abuse has been shown to affect lung immunity, resulting in significant lung injury. There is a paucity of literature on the additive effects of HIV and alcohol, two diseases of immune senescence, in the lung. This chapter begins by discussing the latest literature evaluating the epidemiology of HIV, alcohol use, and lung health focusing on two prevalent infections, tuberculosis and pneumococcal pneumonia. In parallel, we discuss the interactions of alcohol and HIV on the risk for acute lung injury and subsequent morbidity and mortality. We then discuss the pathophysiology of how these two diseases of immune dysfunction affect the lung, with a focus on the oxidative stress, alveolar macrophage host immune capacity, and immunomodulatory role of zinc in the airway. Finally, we review the latest literature on how HIV and alcohol affect other pulmonary disorders including chronic obstructive pulmonary disease, pulmonary hypertension, and lung cancer.

• IK2 CX000643 CSRD VA

The distal airways are covered with a heterogeneous layer of cells known as the alveolar epithelium. Alveolar epithelial cells provide the major barrier between the airspace and fluid filled tissue compartments. As such, regulation of the alveolar epithelium is critical to maintain a healthy lung and for optimal gas exchange. In this chapter, we discuss functional roles for alveolar epithelial cells with particular emphasis on intercellular junctions and communication. As a thin layer of cells directly exposed to atmospheric oxygen, alveoli are particularly sensitive to oxidant insults. Alcohol significantly diminishes the normal antioxidant reserves of the alveolar epithelium, thereby rendering it sensitized for an exaggerated damage response to acute and chronic injuries. The effects of alcohol on alveolar epithelia are discussed along with open questions and potential therapeutic targets to prevent the pathophysiology of alcoholic lung disease.

• pneumocyte
• alveolus
• claudin
• connexin
• tight junction
• gap junction
• ethanol
• barrier function
• pulmonary edema
• fluid clearance

Zinc is one of the most abundant trace elements in the human body, and its presence is essential for numerous biological processes including enzymatic activity, immune function, protein synthesis, and wound healing. Given these important roles, zinc has a sophisticated transport system to regulate its homeostasis. Determination of zinc status, however, is difficult to determine as serum levels are closely maintained and are not an accurate reflection of total body zinc or metabolism at the organ level. Fortunately, the discovery of zinc-specific fluorescent dyes has allowed for a much better assessment of zinc status in the respiratory system and has revealed that alcoholism perturbs this highly developed zinc metabolism such that its distribution to the lung and alveolar space is significantly decreased. As a result, this pulmonary zinc deficiency impairs function in the alveolar macrophage, which is the primary host immune cell within the lower airway. Experimental models have demonstrated that correction of this zinc deficiency restores immune function to the alveolar macrophage as best reflected by improved bacterial clearance in response to infection. While the precise mechanisms underlying alcohol-induced zinc deficiency are still under investigation, there is experimental evidence of several important connections with granulocyte–macrophage colony-stimulating factor and oxidative stress, suggesting that alteration of zinc homeostasis may be a fundamental mechanism underlying the cellular pathology seen in the alcohol lung phenotype. This chapter reviews zinc homeostasis and offers insight into our understanding of zinc deficiency in the setting of alcoholism and the potential of zinc as a therapeutic modality in the vulnerable alcoholic host.

• zinc
• glutathione
• alveolar macrophage
• pneumonia
• phagocytosis
• alcohol
• granulocyte/macrophage colony-stimulating factor (gm-csf)

Chronic alcohol abuse causes oxidative stress and impairs alveolar epithelial barrier integrity, thereby rendering the lung susceptible to acute edematous injury. Experimentally, alcohol-induced oxidative stress increases the expression of transforming growth factor β1 (TGFβ1) in the lung; however, we do not know the precise contribution of various alveolar cells in this process. In the present study, we focused on cell-cell interactions between alveolar macrophages and epithelial cells and the potential mechanisms by which TGFβ1 may become activated in the alveolar space of the alcoholic lung.

Primary alveolar macrophages and epithelial cells were isolated from control- and alcohol-fed Sprague–Dawley rats. Expression of TGFβ1 and the epithelial integrin αvβ6 were examined by real time PCR and either immunocytochemistry or flow cytometry. Alveolar epithelial cells were cultured on transwell supports in the presence of macrophage cell lysate from control- or alcohol-fed rats or in the presence of viable macrophages ± alcohol. Epithelial barrier function was assessed by transepithelial resistance (TER) and paracellular flux of Texas Red dextran.

TGFβ1 expression was increased in alveolar macrophages from alcohol-fed rats, and TGFβ1 protein was predominantly membrane-bound. Importantly, alveolar macrophage cellular lysate from alcohol-fed rats decreased TER and increased paracellular dextran flux in primary alveolar epithelial cell monolayers as compared to the lysates from control-fed rats. Alcohol-induced epithelial barrier dysfunction was prevented by anti-TGFβ1 antibody treatment, indicating the presence of bioactive TGFβ1 in the macrophage lysate. In addition, co-culturing macrophages and epithelial cells in the presence of alcohol decreased epithelial barrier function, which also was prevented by anti-TGFβ1 and anti-αvβ6 treatment. In parallel, chronic alcohol ingestion in vivo, or direct treatment with active TGFβ1 in vitro, increased the expression of αvβ6 integrin, which is known to activate TGFβ1, in alveolar epithelial cells.

Taken together, these data suggest that interactions between alveolar epithelial cells and macrophages contribute to the alcohol-mediated disruption of epithelial barrier function via the expression and activation of TGFβ1 at points of cell-cell contact.

• acute respiratory distress syndrome
• glutathione
• lung
• redox signaling
• oxidative stress

• Acute Lung Injury/drug therapy
• Acute Lung Injury/etiology
• Acute Lung Injury/genetics
• Acute Lung Injury/metabolism
• Acute Lung Injury/pathology
• Alcohol Drinking/adverse effects
• Alcohol Drinking/drug therapy
• Alcohol Drinking/genetics
• Alcohol Drinking/metabolism
• Alcohol Drinking/pathology
• Animals
• Anticarcinogenic Agents/pharmacology
• Blood-Air Barrier/metabolism
• Blood-Air Barrier/pathology
• Cell Line
• Central Nervous System Depressants/adverse effects
• Central Nervous System Depressants/pharmacology
• Ethanol/adverse effects
• Ethanol/pharmacology
• Gene Expression Regulation/drug effects
• Glutathione/genetics
• Glutathione/metabolism
• Humans
• Isothiocyanates
• Male
• NF-E2-Related Factor 2/biosynthesis
• NF-E2-Related Factor 2/genetics
• Oxidative Stress
• Rats
• Rats, Sprague-Dawley
• Response Elements
• Signal Transduction
• Sulfoxides
• Thiocyanates/pharmacology

• P50 AA013757 NIAAA NIH HHS
• R01 AA017627 NIAAA NIH HHS
• P50 AA 013757 NIAAA NIH HHS
• T32 AA013528 NIAAA NIH HHS
• T32 AA 013528 NIAAA NIH HHS

After iron, zinc is the most abundant essential trace metal. Intracellular zinc ([Zn]_i) is maintained across a wide range of cells and species in a tight quota (100 to 500 μM) by a dynamic process of transport, intracellular vesicular storage, and binding to a large number of proteins (estimated at 3-10% of human proteome). As such, zinc is an integral component of numerous metalloenzymes, structural proteins, and transcription factors. It is generally assumed that a vanishingly small component of [Zn]_i, referred to as free or labile zinc, and operationally defined as the pool sensitive to chelation (by agents such as N, N, N’, N’-tetrakis [2-pyridylmethyl] ethylenediamine [TPEN]) and capable of detection by a variety of chemical and genetic sensors, participates in signal transduction pathways. Zinc deficiencies, per se, can arise from acquired (malnutrition, alcoholism) or genetic (mutations in molecules affecting zinc homeostasis, the informative and first example being acrodermatitis enteropathica) factors or as a component of various diseases (e.g., sickle cell disease, cystic fibrosis, sepsis). Hypozincemia has profound effects on developing humans, and all facets of physiological function (neuronal, endocrine, immunological) are affected, although considerably less is known regarding cardiovascular pathophysiology. In this review, we provide an update on current knowledge of molecular and cellular aspects of zinc homeostasis and then focus on implications of zinc signaling in pulmonary endothelium as it relates to programmed cell death, altered contractility, and septic and aseptic injury to this segment of the lung.

• SLC39A14 or ZIP14
• acute lung injury (ALI)
• apoptosis
• metallothionien (MT)
• pulmonary endothelium
• zinc homeostasis