Alcohol Effects on Gene and Cytokine Expression of Human Airway Epithelia

描述(申请人提供)：过量饮酒经常导致组织损伤，导致严重的医疗疾病。长期以来，人们一直认为酗酒者易患多种传染病，特别是肺部感染。呼吸道上皮细胞是第一道防线。它们不仅提供结构屏障和机械防御机制，而且通过分泌各种细胞因子来动员和调节宿主的防御机制，积极响应细菌的攻击。因此，了解酒精对呼吸道上皮细胞的影响对于阐明酒精损伤呼吸道的细胞机制至关重要。我们假设酒精暴露改变了呼吸道上皮细胞对细菌入侵的基因组和细胞因子反应，从而损害了正常的呼吸道防御机制。这些影响可能会使上皮细胞容易受到细菌感染和损伤。R21建议使用一种独特的气液界面气道上皮细胞培养模型和两种强大的基因和细胞因子分析方法来研究酒精对呼吸道上皮细胞基因表达和细胞因子产生的影响。提出三个具体目标如下。具体目的1：用细胞因子多重阵列方法检测酒精对人呼吸道上皮细胞产生细胞因子和趋化因子的影响；特异性目的2：用基因芯片分析酒精对人呼吸道上皮细胞基因表达谱的影响；特异性目标3：研究酒精对呼吸道上皮细胞活性和完整性的影响。通过完成特定的目标，我们希望获得关于酒精如何在分子和细胞水平上导致人类呼吸道损伤的知识，这可能使患者容易受到酒精相关的肺部感染和损伤。这项研究可能为开发潜在的治疗方法来控制或改变酒精滥用的结果提供信息。

DESCRIPTION (provided by applicant): Excessive alcohol intake often causes tissue injury, leading to severe medical disorders. It has long been recognized that alcohol abusers are susceptible to a wide range of infectious diseases, particularly pulmonary infection infections. Airway epithelia represent the first line of defense. They not only provide structural barriers and mechanical defense mechanisms, but also respond actively to bacterial challenge by secreting various cytokines to mobilize and modulate the host defens defense. Therefore, understanding alcohol effects on airway epithelial cells is critical to elucidate the cellular mechanisms of alcohol damage to airways. We hypothesize that alcohol exposure alters genomic and cytokine responses of airway epithelia to bacteri bacterial invasion and thus impairs the normal airway defense al mechanisms. The effects may render the epithelia susceptible to bacterial infection and injury. This R21 proposal is to use one unique air air-liquid interface airway epithelial culture model and two powerful gene and cytokine analysis approaches to investigate how alcohol affects airway epithelial cell gene expressions and cytokine productions. Three specific aims are proposed as follows. Specific Aim 1: to determine the effect of alcohol on cytokine and c chemokine production by human airway epithelial cells hemokine using the cytokine multiplex array approach; Specific Aim 2: to determine the effect of alcohol on gene expression profile of human airway epithelial cells by GeneChip analysis; Specific Aim 3: to study the effects of alcohol on airway epithelial viability and integrity. Through completion of the specific aims, we expect to gain knowledge on how alcohol leads to human airway damage at the molecular and cellular levels, which may predispose patients to al alcohol cohol-associated pulmonary infections and injury. This research may provide information for the development of potential therapeutics to control or modify outcomes of alcohol abuse.