Aldehydes in Alcohol-Induced Organ Injury

说明(申请人提供)：饮酒对身体有毒害作用，主要靶器官为肝脏和大脑。最近的研究表明，酒精所致的器官损伤可能涉及器官与器官之间的相互作用。最广为人知的器官-器官相互作用机制是肠道产生的内毒素(内毒素，LPS)信号。饮酒会导致肠道屏障的破坏，导致内毒素血症，进而通过刺激细胞因子的产生而导致肝-脑轴的组织损伤。乙醛的产生是酒精中毒的一个特征。酒精代谢产生乙醛，而脂质过氧化产生脂醛，如4-羟基壬烯醛(4-HNE)和丙二醛(MDA)。酒精中毒后，在肠道内容物、肝脏、血液和大脑中检测到醛的积累。醛具有细胞毒性，并可能在肠道-肝脏-脑轴介导酒精活动。首先，肠道菌群中乙醛的产生在酒精诱导的肠道屏障破坏和内毒素信号的产生中起关键作用。其次，从肝脏产生的醛已被证明通过使蛋白质失活来介导酒精引起的肝损伤。第三，乙醛清除中的肝功能障碍导致全身乙醛升高，这可能是一种全身因素，介导了酒精所致的脑损伤。在肝脏中，醛主要可以被ALDH解毒，然而，我们的研究表明，尽管慢性酒精暴露后醛积累，但线粒体ALDH(ALDH2)在肝脏中并没有上调。我们还发现，补锌减轻了酒精诱导的肝损伤，并与ALDH2的上调有关。ALDH2的过表达被证明可以减轻线粒体和内质网(ER)应激，从而防止酒精诱导的器官损伤，包括肝脏和脑。这个项目将验证我们的假设，即醛在肠道-肝脏-脑轴上关键地介导了酒精诱导的细胞毒性，从而在酒精诱导的发病机制中是一个系统性因素。目的1确定微生物区系醛的产生在酒精诱导的肠屏障破坏和内毒素信号产生中的作用。肠腔醛对肠道紧密连接、血液内毒素和肝-脑损伤的影响将被确定。肠腔内容物和上皮细胞的代谢变化也将被测量。目的2确定肝醛生成在酒精性肝损伤中的意义。醛对肝脏脂质平衡和促炎细胞因子产生的影响将被确定。醛和脂多糖在促炎细胞因子产生中的相互作用也将被测量。醛与酒精诱导的肝脏代谢和蛋白质组改变的机制联系将被识别。目的3确定肝源性乙醛信号在酒精性脑损伤中的意义。肝功能障碍和体液醛升高之间的联系将被明确。肝脏产生的乙醛信号在酒精诱导的脑损伤中的作用将被确定。目的4探讨乙醛毒性和除醛治疗的分子机制。乙醛-蛋白质加合物在肠道-肝脏-脑轴的形成将被确定。ALDH2重组嗜酸乳杆菌、锌和白藜芦醇对乙醛清除和酒精诱导的器官损伤的影响将被确定。PHS 398/2590(06/09版)页面续格式页面 与公共卫生相关：酒精中毒会导致多器官损伤，但FDA批准的有效治疗方法尚不存在。酒精代谢会产生具有细胞毒性的醛。在肠道中产生的醛会破坏肠道屏障，导致内毒素血症，从而引发炎症。肝醛清除功能障碍会引起醛在肝脏和血液中的蓄积，导致多器官损伤。这个项目将确定乙醛作为一种系统因子在介导酒精引起的肠道-肝脏-脑轴组织损伤中的作用。这项研究不仅将促进我们对酒精诱导的发病机制的认识，还将提示除醛作为一种潜在的治疗策略用于治疗酒精诱导的疾病。

DESCRIPTION (provided by applicant): Alcohol consumption exerts toxic effects on the body with liver and brain as the major target organs. Recent studies suggest that alcohol-induced organ injury may involve organ-organ interactions. The most well-known mechanism underlying organ-organ interactions is gut-generated endotoxin (lipopolysaccharide, LPS) signal. Alcohol consumption causes gut barrier disruption, leading to endotoxemia, which, in turn, causes tissue injury at the liver-brain axis by stimulating cytokine production. Aldehyde generation is a feature of alcohol intoxication. While alcohol metabolism generates acetaldehyde, lipid peroxidation produces lipid aldehydes such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Accumulation of aldehydes has been detected in intestinal contents, liver, blood and brain after alcohol intoxication. Aldehydes are cytotoxic, and may mediate alcohol actions at the gut-liver-brain axis. First, acetaldehyde generation from the gut microflora critically mediate alcohol-induced gut barrier disruption and generation of LPS signal. Second, aldehydes generated from the liver have shown to mediate alcohol-induced liver injury by inactivating proteins. Third, liver dysfunction in aldehyde clearance results in systemic aldehyde elevation, which may act as a systemic factor and mediate alcohol-induced brain damage. Aldehydes can be detoxified primarily by ALDH in the liver, however, our studies showed that mitochondrial ALDH (ALDH2) was not up-regulated in the liver despite aldehyde accumulation after chronic alcohol exposure. We also found that zinc supplementation attenuated alcohol-induced liver injury in association with up-regulation of ALDH2. Over-expression of ALDH2 has been shown to attenuate mitochondrial and endoplasmic reticulum (ER) stress, thereby preventing alcohol-induced organs injury including liver and brain. This project will test our hypothesis that aldehydes critically mediate alcohol-induced cytotoxicity at the gut-liver-brain axis, thereby being a systemic factor in alcohol-induced pathogenesis. Aim 1 is to define the role of microbiota aldehyde generation in alcohol-induced gut barrier disruption and generation of LPS signal. Effects of gut luminal aldehydes on gut tight junctions, blood LPS and liver-brain injury will be determined. Metabolic alterations in the gut luminal contents and epithelium will also be measured. Aim 2 is to determine the significance of hepatic aldehyde generation in alcohol-induced liver injury. Effects of aldehydes on hepatic lipid homeostasis and pro-inflammatory cytokine production will be determined. Interaction between aldehydes and LPS in pro-inflammatory cytokine production will also be measured. Mechanistic link of aldehydes with alcohol-induced metabolomic and proteomic alterations in the liver will be identified. Aim 3 is to determine the significance of liver-generated aldehyde signal in alcohol-induced brain injury. The link between liver dysfunction and systemic aldehyde elevation will be defined. The role of liver- generated aldehyde signal in alcohol-induced brain injury will be determined. Aim 4 is to explore the molecular mechanism of aldehyde toxicity and aldehyde removal therapies. Formation of aldehyde-protein adducts at the gut-liver-brain axis will be identified. Effects of ALDH2-recombinant L. acidophilus, zinc and resveratrol on aldehyde clearance and alcohol-induced organ injury will be determined. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Alcohol intoxication causes multiple organ injury, but FDA-approved effective therapy is not available. Alcohol metabolism generates aldehydes which are cytotoxic. Aldehyde generation in the intestine disrupts gut barrier, leading to endotoxemia which triggers inflammation. Liver dysfunction in aldehyde clearance will cause aldehyde accumulation in the liver and blood, leading to multiple organ injury. This project will define the role of aldehyde as a systemic factor in mediating alcohol-induced tissue damage at the gut-liver-brain axis. The proposed research will not only advance our knowledge on alcohol-induced pathogenesis, but also suggest the removal of aldehydes as a potential therapeutic strategy for treatment of alcohol-induced diseases.