Alcohol Abuse, the Alveolar Macrophage and Pneumonia

Mehta, Ashish J.; Guidot, David M.; Weber, Karl T.

doi:10.1097/maj.0b013e31823ede77

Cited by 52 publications

(53 citation statements)

References 19 publications

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“…Instead in males, retinoate biosynthesis was targeted, likely reflecting the increased levels of retinoic acid observed after chronic ethanol treatment (Kane et al, 2010), and the involvement of alcohol and aldehyde dehydrogenase in retinol catalysis (see Pino-Lagos et al, 2008). Interestingly, retinoic acid reduces production of inflammatory mediators from peritoneal macrophages in response to lipopolysaccharide (Mehta and Guidot, 2012). During the abstinence phase, analysis identified atherosclerosis signaling as the top pathway in the low response WSR model.…”

Section: Discussionmentioning

confidence: 99%

Understanding the addiction cycle: A complex biology with distinct contributions of genotype vs. sex at each stage

Wilhelm

Hashimoto

Roberts³

et al. 2014

Neuroscience

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Ethanol abuse can lead to addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. There is evidence for contributions of both genotype and sex to alcoholism, but an understanding of the biological underpinnings is limited. Utilizing both sexes of genetic animal models with highly divergent alcohol withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) mice, the distinct contributions of genotype/phenotype and of sex during addiction stages on neuroadaptation were characterized. Transcriptional profiling was performed to identify expression changes as a consequence of chronic intoxication in the medial prefrontal cortex. Significant expression differences were identified on a single platform and tracked over a behaviorally-relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more sensitive to ethanol with higher fold expression differences. Bioinformatics showed a strong effect of sex on the data structure of expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, differences were observed instead between the lines/phenotypes irrespective of sex. Confirmation of identified pathways showed distinct inflammatory signaling following intoxication at peak withdrawal, with a pro-inflammatory phenotype in females but overall suppression of immune signaling in males. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of stage- and sex-specific therapies for alcohol withdrawal and the maintenance of sobriety.

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Section: Discussionmentioning

confidence: 99%

Understanding the addiction cycle: A complex biology with distinct contributions of genotype vs. sex at each stage

Wilhelm

Hashimoto

Roberts³

et al. 2014

Neuroscience

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“…However, it is likely that other defects within mice chronically consuming EtOH (such as IL-2 expression by CD4 T cells and defects within APCs) contribute to inappropriate and/or insufficient priming of IAV-specific CD8 T cells within dLN. Changes in antigen presenting cell populations have been well documented to occur during EtOH exposure (Fan et al, 2011, Ness et al, 2008, Parlet and Schlueter, 2013, Edsen-Moore et al, 2008, Legge and Waldschmidt, 2014, Gurung et al, 2009, Buttari et al, 2008, Happel and Nelson, 2005, Joshi and Guidot, 2007, Szabo and Mandrekar, 2009, Zhang et al, 2002, Eken et al, 2011, Joshi et al, 2005, Lau et al, 2007, Mehta and Guidot, 2012, Rendon et al, 2012, Siggins et al, 2009, Szabo and Mandrekar, 2008). While dendritic cell functionality during IAV challenge of mice chronically consuming EtOH has not been completely investigated, the migration of dermal DCs, cutaneous DCs and Langerhans cells is delayed following FITC sensitization (Ness et al, 2008, Parlet and Schlueter, 2013).…”

Section: Discussionmentioning

confidence: 99%

Chronic Ethanol Exposure Selectively Inhibits the Influenza‐Specific CD8 T Cell Response During Influenza A Virus Infection

Hemann

McGill

Legge

2014

Alcoholism Clin & Exp Res

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Background It is well established that chronic ethanol (EtOH) consumption is associated with increased incidence and disease severity of respiratory infections. Our recent work demonstrates this increase in disease severity to influenza virus (IAV) infections is due, in part, to a failure to mount a robust IAV-specific CD8 T cell response along with a specific impairment in the ability of these T cells to produce IFNγ. However, the full extent of the lesion in the effector CD8 T cell compartment during chronic EtOH consumption remains unknown. Methods Utilizing the Meadows-Cook murine model of chronic alcohol consumption, mice received EtOH in their drinking water for 8 or 12 weeks. Mice were challenged intranasally with IAV and the activation and effector functions of IAV specific CD8 T cells were determined in both the lung-draining lymph nodes and lungs. Results Our results confirm the defect in interferon γ (IFNγ) production, however, the ability of IAV-specific T cells to produce tumor necrosis factor α (TNFα) and interleukin-2 (IL-2) in EtOH-consuming mice remains unaltered while interferon γ (IFNγ) production. In contrast, EtOH consumption significantly reduces the ability of CD8 T cells to degranulate and kill IAV-specific targets. Finally, our findings suggest the lesion begins during the initial activation of CD8 T cells, as we observe early defects in proliferation in the lung-draining lymph nodes (dLN) of IAV-infected, EtOH-consuming mice. Conclusions These findings highlight the previously unrecognized depth of the lesion in the IAV-specific CD8 T cell response during chronic EtOH consumption. Given the important role CD8 T cell immunity plays in control of IAV, these findings may aid in the development of vaccination and/or therapeutic strategies to reverse these defects in the CD8 T cell response and reduce serious disease outcomes associated with IAV infections in alcoholics.

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“…Subjects with alcohol use disorders have an increased risk of developing respiratory infections, such as pneumonia (49). We next examined whether the ethanol-induced suppression of AM phagocytosis was physiologically relevant, resulting in an increased risk of respiratory infections, and whether GSH reversed these effects.…”

Section: -E)mentioning

confidence: 99%

“…glutathione; alveolar macrophage; nicotinamide adenine dinucleotide phosphate oxidases; oxidative stress; phagocytic function CHRONIC ALCOHOL ABUSE INCREASES susceptibility to acute respiratory distress syndrome (ARDS) (54), a severe form of lung injury with a 26% mortality rate (23), and increases risk of developing respiratory infections, such as pneumonia (49). ARDS is characterized by the development of pulmonary inflammation and edema in response to aspiration, sepsis, or trauma, resulting in systemic proinflammatory cascade activation (68).…”

mentioning

confidence: 99%

Glutathione attenuates ethanol-induced alveolar macrophage oxidative stress and dysfunction by downregulating NADPH oxidases

Yeligar

Harris

Hart

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Chronic alcohol abuse increases lung oxidative stress and susceptibility to respiratory infections by impairing alveolar macrophage (AM) function. NADPH oxidases (Nox) are major sources of reactive oxygen species in AMs. We hypothesized that treatment with the critical antioxidant glutathione (GSH) attenuates chronic alcohol-induced oxidative stress by downregulating Noxes and restores AM phagocytic function. Bronchoalveolar lavage (BAL) fluid and AMs were isolated from male C57BL/6J mice (8 -10 wk) treated Ϯ ethanol in drinking water (20% wt/vol, 12 wk) Ϯ orally gavaged GSH in methylcellulose vehicle (300 mg·kg Ϫ1 ·day Ϫ1 , during week 12). MH-S cells, a mouse AM cell line, were treated Ϯ ethanol (0.08%, 3 days) Ϯ GSH (500 M, 3 days or last 1 day of ethanol). BAL and AMs were also isolated from ethanol-fed and control mice Ϯ inoculated airway Klebsiella pneumoniae (200 colony-forming units, 28 h) Ϯ orally gavaged GSH (300 mg/kg, 24 h). GSH levels (HPLC), Nox mRNA (quantitative RT-PCR) and protein levels (Western blot and immunostaining), oxidative stress (2=,7=-dichlorofluorescein-diacetate and Amplex Red), and phagocytosis (Staphylococcus aureus internalization) were measured. Chronic alcohol decreased GSH levels, increased Nox expression and activity, enhanced oxidative stress, impaired phagocytic function in AMs in vivo and in vitro, and exacerbated K. pneumonia-induced oxidative stress. Although how oral GSH restored GSH pools in ethanol-fed mice is unknown, oral GSH treatments abrogated the detrimental effects of chronic alcohol exposure and improved AM function. These studies provide GSH as a novel therapeutic approach for attenuating alcohol-induced derangements in AM Nox expression, oxidative stress, dysfunction, and risk for pneumonia. glutathione; alveolar macrophage; nicotinamide adenine dinucleotide phosphate oxidases; oxidative stress; phagocytic function CHRONIC ALCOHOL ABUSE INCREASES susceptibility to acute respiratory distress syndrome (ARDS) (54), a severe form of lung injury with a 26% mortality rate (23), and increases risk of developing respiratory infections, such as pneumonia (49). ARDS is characterized by the development of pulmonary inflammation and edema in response to aspiration, sepsis, or trauma, resulting in systemic proinflammatory cascade activation (68). Compared with a 22% incidence of ARDS in nonalcoholic patients at risk for lung injury, alcoholic patients have a 43% incidence of ARDS (52). Alcohol predisposes to ARDS development through multiple mechanisms, including oxidative stress (11,33,35,37,52). Furthermore, subjects with a history of alcohol use disorders have a higher prevalence of community-acquired pneumonia (20), resulting in worse clinical outcomes than nonalcoholics. Chronic alcohol ingestion increases oxidative stress, which primes the lung for respiratory infections and injury (34).Chronic alcohol consumption depleted levels of the critical antioxidant glutathione (GSH) in the bronchoalveolar lavage (BAL) fluid of human subjects (53) and in the alveolar macro...

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Alcohol Abuse, the Alveolar Macrophage and Pneumonia

Cited by 52 publications

References 19 publications

Understanding the addiction cycle: A complex biology with distinct contributions of genotype vs. sex at each stage

Understanding the addiction cycle: A complex biology with distinct contributions of genotype vs. sex at each stage

Chronic Ethanol Exposure Selectively Inhibits the Influenza‐Specific CD8 T Cell Response During Influenza A Virus Infection

Glutathione attenuates ethanol-induced alveolar macrophage oxidative stress and dysfunction by downregulating NADPH oxidases

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