Pulmonary Disfunction after Polysubstance Exposure: Mechanistic Identification of Inflammatory Mediators

摘要 酒精和大麻(大麻素)是全世界普遍滥用的药物，青少年 这两种药物的共同暴露/共同滥用的特点是高水平的共同发病率。都是慢性的 大量摄入酒精和大麻素会增加急性肺损伤(ALI)的风险，而且两者都有 社区和卫生保健相关肺炎(分别为CAP和HAP)，导致 发病率和死亡率。我们最近使用了一种青少年间歇性酒精中毒的小鼠模型。 (AIE)和大麻素(AIC)暴露，以检查成人肺过度暴露的作用 炎症，我们的数据表明，先前接触多物质会导致增加 HMGB1表达与微生物所致肺部炎症有趣的是，我们的体外研究 表明酒精和大麻素都能激活巨噬细胞HMGB-1的表达，并且 抑制细胞上的大麻素受体CB1R和CB2R抑制HMGB-1的表达，并 使用CB1R拮抗剂在体内进行了概述。我们的目标是研究CBR信号作为一种潜在的 对酒精和大麻素依赖的肺部炎症的治疗方向。

Abstract Alcohol and marijuana (cannabinoids) are commonly abused drugs worldwide, and adolescent co-exposure/co-abuse of these two drugs is hallmarked by high levels of co-morbidity. Both chronic binge ethanol and cannabinoid consumption enhances the risk of acute lung injury (ALI) and both community and health care associated pneumonia (CAP and HAP, respectively), leading to increased morbidity and mortality. We have recently utilized a mouse model for adolescent intermittent ethanol (AIE) and cannabinoid (AIC) exposure to examine roles of binge exposure to adult-pulmonary inflammation, and our data suggests that that the prior polysubstance exposure leads to increased HMGB1 expression and microbial-induced pulmonary inflammation. Interestingly, our in vitro studies indicate that both alcohol and cannabinoids activate HMGB-1 expression from macrophage cells, and inhibiting cannabinoid receptors CB1R and CB2R on cells inhibits HMGB-1 expression, and is recapitulated in vivo using antagonists for CB1R. We aim to investigate CBR signaling as a potential therapeutic direction in response to alcohol and cannabinoid-dependent pulmonary inflammation.