Dataset Information

Alcohol-dependent pulmonary inflammation: A role for HMGB-1.

ABSTRACT: Previous studies have demonstrated that acute alcohol intoxication significantly impairs lung immune responses, which can lead to the tissue being undefended from microbial infection and resulting disease. Data suggest that acute intoxication presents an axis where simultaneously suppressing early pro-inflammatory cytokines while inducing anti-inflammatory signals contributes to alcohol-dependent immune suppression in the lung, and thus undeterred microbial replication. Interestingly, alcoholics and those with alcohol use disorder present with increased pneumonia and acute respiratory diseases (ARDs), suggesting a more active priming of inflammatory responses in the lungs. There is current research evaluating the acute effects of binge ethanol consumption on adolescents, which is of grave concern, though long-term effects of adolescent ethanol binge exposure are less studied. We hypothesize that adolescent binge drinking may prime the individual to severe pulmonary distress, when later challenged by a microbial pathogen. Herein, we evaluate a model of adolescent intermittent ethanol (AIE) exposure to investigate pulmonary pathology after microbial challenge. Ethanol was administered to adolescent mice using a binge exposure schedule, and mice were then rested to early adulthood. These mice were then challenged with a sub-lethal intranasal inoculation of Klebsiella pneumoniae and evaluated for severity of disease. We find that AIE exposure initially activates inflammatory mediators within the lung, which resolves over time. However, when challenged with a microbial pathogen after this resolution period, these animals present with more severity of inflammation, pulmonary tissue damage, and mortality when challenged with a pulmonary microbial infection. Interestingly, our data suggest a role for alcohol-dependent release of the protein HMGB-1 from host cells, for both morbidity and mortality in our model of microbial-dependent pulmonary inflammation.

SUBMITTER: Harris B

PROVIDER: S-EPMC6443509 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Alcohol-dependent pulmonary inflammation: A role for HMGB-1.

Harris Brianna B Mcalister Akeem A Willoughby Tacriasha T Sivaraman Vijay V

Alcohol (Fayetteville, N.Y.) 20181002

Previous studies have demonstrated that acute alcohol intoxication significantly impairs lung immune responses, which can lead to the tissue being undefended from microbial infection and resulting disease. Data suggest that acute intoxication presents an axis where simultaneously suppressing early pro-inflammatory cytokines while inducing anti-inflammatory signals contributes to alcohol-dependent immune suppression in the lung, and thus undeterred microbial replication. Interestingly, alcoholics ...[more]

PMID: 30287211

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Project description:Brain abnormalities observed in alcohol use disorder are highly heterogeneous in nature and severity, possibly because chronic alcohol consumption also affects peripheral organs leading to comorbidities that can result in exacerbated brain alterations. Despite numerous studies focussing on the effects of alcohol on the brain or liver, few studies have simultaneously examined liver function and brain damage in alcohol use disorder, and even fewer investigated the relationship between them except in hepatic encephalopathy. And yet, liver dysfunction may be a risk factor for the development of alcohol-related neuropsychological deficits and brain damage well before the development of liver cirrhosis, and potentially through inflammatory responses. The use of animal models enables a better understanding of the pathophysiological mechanisms underlying liver-brain relationships in alcohol use disorder, and more particularly of the inflammatory response at the tissue, cerebral and hepatic levels. The objective of this translational study was to investigate, both in alcohol use disorder patients and in a validated animal model of alcohol use disorder, the links between peripheral inflammation, liver damage and brain alterations. To do this, we conducted an in vivo neuroimaging examination and biological measures to evaluate brain volumes, liver fibrosis and peripheral cytokines in alcohol use disorder patients. In selectively bred Sardinian alcohol-preferring rats, we carried out ex vivo neuroimaging examination and immunohistochemistry to evaluate brain and liver inflammatory responses after chronic (50 consecutive weeks) alcohol drinking. In recently abstinent and non-cirrhotic alcohol use disorder patients, the score of liver fibrosis positively correlated with subcortical regions volumes (especially in right and left putamen) and level of circulating proinflammatory cytokines. In Sardinian alcohol-preferring rats, we found macrostructural brain damage and microstructural white matter abnormalities similar to those found in alcohol use disorder patients. In addition, in agreement with the results of peripheral inflammation observed in the patients, we revealed, in Sardinian alcohol-preferring rats, inflammatory responses in the brain and liver were caused by chronic alcohol consumption. Since the liver is the main source of cytokines in the human body, these results suggest a relationship between liver dysfunction and brain damage in alcohol use disorder patients, even in the absence of major liver disease. These findings encourage considering new therapeutic strategies aiming at treating peripheral organs to limit alcohol-related brain damage.

Dataset Information

Alcohol-dependent pulmonary inflammation: A role for HMGB-1.

Publications

Alcohol-dependent pulmonary inflammation: A role for HMGB-1.

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