Chronic ingestion of alcohol modulates expression of ubiquitin editing enzyme A20 in lung macrophages

Abstract

BackgroundAlcohol abuse is involved in the pathogenesis of multiple organ disorders; the underlying mechanism is incompletely understood. The ubiquitin editing enzyme A20 is involved in regulating activities in the cell. Suppression of A20 is suggested as one factor in the initiation of inflammation. This study investigates the mechanism by which chronic alcohol consumption modulates the levels of ubiquitin editing enzyme A20 in macrophages and further contributes to induce endothelial barrier dysfunction in the lung.MethodsMice were gavage-fed with 40% alcohol daily for 0-3 weeks. Airway macrophages were collected by lung lavage. Expression of ubiquitin editing enzyme A20 in isolated macrophages was assessed at both mRNA and protein levels. The endothelial barrier function of the lung was evaluated by the Evans blue method.ResultsMice treated with alcohol for 3 weeks showed an increase in cell infiltration in the lung in response to exposure to peptidoglycan; over 80% of the infiltrated cells were macrophages. Furthermore, we observed that A20 level was suppressed in macrophages of mice treated with alcohol; the levels of tumor necrosis factor, interleukin-6 and nuclear factor kappa B in macrophage were increased. In addition, the endothelial barrier function of the lung was compromised, showing excessive infiltration of Evans blue in the lung indicating lung edema. Pretreatment with synthesized A20 inhibited alcohol-induced lung endothelial barrier dysfunction.ConclusionsWe conclude that chronic alcohol ingestion disturbs the endothelial barrier function in the lung by modulating macrophage properties. Increase in A20 in the cell may have potential for the treatment of inflammatory disorders.

Alveolar macrophage inflammatory mediator expression is elevated in the setting of alcohol use disorders

“…The balance between the induction of pro-inflammatory mediators and antioxidant genes in response to oxidative stress, especially oxidative stress induced by chronic alcohol ingestion, requires further study (Moodie et al, 2004; Rahman, 1999). Other mechanisms for this prolonged pro-inflammatory state have been suggested as well, including chronic suppression of factors that restrict NFκB activities in alveolar macrophages as described by Huang, et al (Huang, Chen, & Liu, 2011). …”

The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease

“…Significantly, to overcome those obstacles, the focus should be put on molecular basic research and understanding the still not elucidated molecular factors, crosstalks with other pathways and, most importantly, different regulators. Interestingly, in Huang et al, the levels of the A20 protein were diminished in lung macrophages isolated from alcoholic mice models in the chronic setting, while the levels of pro-inflammatory cytokines increased [ 239 ]. This suggests an important role of A20 in the inhibition of the inflammation in alcohol-induced organ damage, however, further experimental evidence is necessary to proceed.…”