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：
9017894
负责人：
RONALD JOHN KORTHUIS
金额：
$ 34.12万
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/9017894
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 Integrin alphaVbeta3 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 TNF gene TNFRSF1A gene TRPV1 gene Therapeutic Tissues Tumor Tissue Vascular blood supply Wild Type Mouse Work adenylate kinase alcohol exposure base heme oxygenase-1 insight neutrophil novel novel therapeutics patient population postcapillary venule preconditioning prevent problem drinker programs protein function psychosocial 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-� (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-� (TNF). TNF-dependent, neutrophil proteasemediated generation of signals in the interstitium engage endothelial integrin �v�3 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, �v�3 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 �v�3-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（由适用提供）：在低至中等水平的乙醇（ETOH）定期消费保护器官和微脉管系统免受缺血和再灌注的有害影响（I/R）。最近，我们发现，先前的乙醇摄入会引起抗炎表型的发展（减少了炎症介质的牙后形成，并显着减弱了粘合分子的表达，氧化剂的产生和白细胞的产生和白细胞滚动，粘附，粘附，以及在后质量剂量的机制中的粘附因素，该机制因素造成的机制因素而在繁殖后的迁移因素而产生的机制因素，并在现有的机械方面存在生产的造成范围的造成范围的造成的生产效果。疾病。令人惊讶的是，我们的工作发现了促炎钙蛋白基因相关的肽（CGRP）和肿瘤坏死因子 - （TNF）在乙醇暴露期间介导的中性粒细胞激活在启动这种适应性转化的过程中的重要作用。在当前的提案中，我们试图基于这些基本观察结果，以评估每天中度ETOH诱导TRPV1依赖性CGRP从感觉神经元释放的总体假设，这又激活CD4+ T淋巴细胞以表达肿瘤坏死因子 - （TNF）。 TNF依赖性的中性粒细胞蛋白酶蛋白酶介导的内部互动内皮整合素中的信号生成 - v。3，以诱导HO-1表达/活性增加以限制缺血后的微血管功能障碍。为了解决这一假设，我们建议确定：（1）ETOH诱导的T淋巴细胞的CGRP依赖性激活，随后产生了TNF来激活组织居民中性粒细胞以产生蛋白质的信号，从而引发对抗毒性现象的抗激素现象乙醇乙烷的抗激发性乙烷的信号；（2）中性粒细胞蛋白酶引起的，v。v。v。依赖性蛋白依赖性增加了HO-1的表达和活性，作为在I/R期间看到的抗炎表型的下游介体。插入性微观方法将用于量化缺血后白细胞/内皮细胞相互作用。 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 Significance: This work will identify new links between CGRP-activated T cells, signals generated by the proteolytic activity of TNF-activated neutrophils, and �v�3-dependent HO-1 expression/activity in通过摄入前乙醇对I/R的耐受性。完成这些研究将为相关患者人群中翻译治疗的发展提供机械基础。