Impact of chronic alcohol consumption on the functional and epigenetic landscapes of monocytes and their progenitors

总结 慢性重度饮酒（CHD）与多种不良健康结果相关，包括增加 肝病、心血管疾病、癌症和/或传染病的发病率。鉴于增加 冠心病患者中常见的病毒、细菌和/或真菌感染的发生率，这表明酒精 可对宿主免疫应答和宿主防御产生显著影响。几项研究表明 由CHD诱导的最显著和一致的变化在先天免疫臂中是明显的。 非人灵长类动物（NHP）自愿乙醇自我管理模型，我们报告了显着的缺陷 在单核细胞/巨噬细胞中。冠心病还与呼吸道感染和疾病的风险增加有关， 特别是急性呼吸窘迫综合征（ARDS）。肺泡巨噬细胞在细胞凋亡中起关键作用。 与ARDS相关的炎症过程。最近，我们报道肺泡巨噬细胞 从CHD猕猴表现出增加的氧化损伤的迹象，产生夸张的炎症反应， 反应，并抑制抗细菌和抗病毒免疫反应;从而提供了一个联系， CHD和ARDS发病率增加。然而，确切的机制仍然知之甚少。目的 这种多样性补充是为了支持杰米斯特吉尔博士测试的假设，失调的 CHD肺泡巨噬细胞神经酰胺水平和信号传导导致炎症反应加剧 应答Sturgill实验室以前的工作表明，神经酰胺是肺中的关键鞘脂， 神经酰胺信号的改变导致活性氧产生增加，巨噬细胞炎症 反应、细胞凋亡和肺功能障碍。此外，神经酰胺水平增加的患者， 酒精性肝病因此，神经酰胺是一个合乎逻辑的研究目标。这一补充符合 亲本R 01，其正在研究循环单核细胞的异常炎症机制。这 补充将使Sturgill博士能够在一个有重点和有指导的项目中解决我们知识中的关键差距 同时磨练技术技能，并获得酒精和免疫领域的专业知识，以促进她 能够提交R 01提案，以进一步询问CHD对肺部疾病的影响。

SUMMARY Chronic heavy drinking (CHD) is associated with multiple adverse health outcomes including increased incidence of liver disease, cardiovascular disease, cancer, and/or infectious disease. Given the increased incidence of viral, bacterial, and/or fungal infections often seen in patients with CHD, this suggests that alcohol can have a significant impact on the host immune response and host defense. Several studies have shown that the most dramatic and consistent changes induced by CHD are evident in the innate immune arm. Using a non-human primate (NHP) model of voluntary ethanol self-administration, we have reported significant defects in monocytes/macrophages. CHD is also associated with increased risk for respiratory infection and disease, notably acute respiratory distress disease syndrome (ARDS). Alveolar macrophages play a critical role in the inflammatory process associated with ARDS. More recently, we have reported that alveolar macrophages from CHD macaques exhibit signs of increased oxidative damage, generate an exaggerated inflammatory response, and dampened anti-bacterial and anti-viral immune responses; thereby providing a link between CHD and increased incidence of ARDS. However, exact mechanisms remain poorly understood. The purpose of this diversity supplement is to support Dr. Jamie Sturgill to test the hypothesis that dysregulation of ceramide levels and signaling in alveolar macrophage with CHD leads to exacerbated inflammatory responses. Previous work by the Sturgill lab has shown that ceramide is a critical sphingolipid in the lung and that alterations of ceramide signaling lead to increased reactive oxygen production, macrophage inflammatory responses, apoptosis, and pulmonary dysfunction. Moreover, ceramide levels are increased in patients with alcoholic liver disease. Thus, ceramide is a logical target to investigate. This supplement is in line with the parent R01 that is investigating mechanisms of aberrant inflammation by circulating monocytes. This supplement will allow Dr. Sturgill to address a critical gap in our knowledge in a focused and mentored project while honing technical skills and gaining expertise in the field of alcohol and immunity in order to facilitate her ability to submit an R01 proposal to further interrogate the effects of CHD on pulmonary disease.