Daily Moderate Ethanol Ingestion Attenuates Postischemic Microvascular Dysfunctio

每日适量摄入乙醇可减轻缺血后微血管功能障碍

基本信息

批准号：
8757257
负责人：
RONALD JOHN KORTHUIS
金额：
$ 34.13万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8757257
关键词：
Address Adenosine A2 Receptors Adhesions Adhesives Afferent Neurons Age Alcohol consumption Alcoholic Beverages Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Attenuated Biochemical Blood flow Bone Marrow Brain CD4 Positive T Lymphocytes Calcitonin Gene-Related Peptide Calcium Cardiovascular Diseases Cell Adhesion Molecules Cell Communication Cell Survival Data Development Dose Emigrations Endothelial Cells Ethanol Event Exposure to Extracellular Matrix Future Gelatinase B Generations Health Heart Hour Inflammation Inflammation Mediators Ingestion Integrins Intestines Investigation Ischemia Knock-out Knockout Mice Leukocyte Rolling Leukocytes Ligand Binding Link Mediating Mediator of activation protein Microscopic Microvascular Dysfunction Mus Necrosis Neutrophil Activation Organ Oxidants Participant Peptide Hydrolases Phenotype Plasma Potassium Production Proteins Publishing Reperfusion Injury Reperfusion Therapy Risk Factors Role Signal Pathway Signal Transduction T-Lymphocyte TNFRSF1A gene TRPV1 gene Therapeutic Tissues Tumor Necrosis Factor-alpha Tumor Tissue Vascular blood supply Wild Type Mouse Work adenylate kinase alcohol exposure base heme oxygenase-1 insight neutrophil novel patient population postcapillary venule preconditioning prevent problem drinker programs protein function psychosocial receptor reconstitution response

项目摘要

DESCRIPTION (provided by applicant): Regular consumption of ethanol (EtOH) at low to moderate levels protects organs and microvasculature from the deleterious effects of ischemia and reperfusion (I/R). Recently, we discovered that antecedent ethanol ingestion provokes the development of an anti-inflammatory phenotype (reduced postischemic formation of inflammatory mediators and markedly attenuated adhesion molecule expression, oxidant production, and leukocyte rolling, adhesion, and emigration in postcapillary venules) via a novel mechanism that remains effective in the presence of co-existing risk factors for cardiovascular disease. Surprisingly, our work uncovered important roles for proinflammatory calcitonin gene-related peptide (CGRP) and tumor necrosis factor-α(TNF) mediated neutrophil activation during the period of ethanol exposure in initiating this adaptive transformation that becomes apparent in postcapillary venules when tissues are exposed to I/R 24 hrs after EtOH. In the current proposal, we seek to build on these fundamental observations to evaluate the overall hypothesis that daily moderate EtOH induces TRPV1-dependent CGRP release from sensory neurons, which in turn activates CD4+ T lymphocytes to express tumor necrosis factor-α (TNF). TNF-dependent, neutrophil proteasemediated generation of signals in the interstitium engage endothelial integrin αvß3 to induce increased HO-1 expression/activity to limit postischemic microvascular dysfunction. To address this postulate, we propose to determine the roles of: (1) EtOH-induced, CGRP-dependent activation of T lymphocytes, which subsequently produce TNF to activate tissue resident neutrophils to proteolytically generate signals that trigger the development of an anti-inflammatory phenotype in response to antecedent ethanol; and (2) neutrophil protease-initiated, αvß3 integrin-dependent increased HO-1 expression and activity as downstream mediators of the anti-inflammatory phenotype seen during I/R. Intravital microscopic approaches will be used to quantify postischemic leukocyte/endothelial cell interactions. The effects of EtOH to elevate plasma and tissue CGRP and TNF levels, induce T cell and neutrophil activation, and increase HO-1 expression and activity to prevent I/R-induced endothelial adhesion molecule and inflammatory mediator expression will also be investigated. Significance: This work will identify new links between CGRP-activated T cells, signals generated by the proteolytic activity of TNF-activated neutrophils, and αvß3-dependent HO-1 expression/activity in the acquisition of tolerance to I/R by antecedent ethanol ingestion. Completing these studies will provide the mechanistic basis for development of translational therapeutics in relevant patient populations.

描述（由申请人提供）：定期摄入低至中等水平的乙醇 (EtOH) 可保护器官和微脉管系统免受缺血和再灌注 (I/R) 的有害影响。抗炎表型（减少缺血后炎症介质的形成，并显着减弱粘附分子的表达、氧化剂的产生和白细胞令人惊讶的是，我们的工作揭示了促炎降钙素基因相关肽（CGRP）和肿瘤坏死的重要作用。因子-α (TNF) 在乙醇暴露期间介导中性粒细胞活化，启动这种适应性转变，当组织暴露于乙醇时，这种适应性转变在毛细血管后微静脉中变得明显EtOH 后 24 小时 I/R 在当前的提案中，我们寻求在这些基本观察的基础上评估总体假设，即每日适量的 EtOH 会诱导感觉神经元释放 TRPV1 依赖性 CGRP，进而激活 CD4+ T 淋巴细胞表达肿瘤。坏死因子-α (TNF) 依赖于中性粒细胞蛋白酶介导的间质信号生成，与内皮整合素 αvß3 结合以诱导增加。 HO-1 表达/活性限制缺血后微血管功能障碍为了解决这一假设，我们建议确定以下作用：（1）EtOH 诱导的 CGRP 依赖性 T 淋巴细胞激活，随后产生 TNF 激活组织驻留中性粒细胞蛋白水解产生信号，触发抗炎表型的发展，以响应先前的乙醇；和（2）中性粒细胞蛋白酶启动的αvß3；整合素依赖性增加的 HO-1 表达和活性作为 I/R 期间观察到的抗炎表型下游介质，将用于量化缺血后白细胞/内皮细胞相互作用。和 TNF 水平，诱导 T 细胞和中性粒细胞活化，并增加 HO-1 表达和活性，以防止 I/R 诱导的内皮粘附分子和炎症介质表达。意义：这项工作将确定 CGRP 激活的 T 细胞、TNF 激活的中性粒细胞的蛋白水解活性产生的信号以及获得 I/R 耐受性中的 αvß3 依赖性 HO-1 表达/活性之间的新联系。完成这些研究将为相关患者群体的转化疗法的开发提供机制基础。