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

• 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
• 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

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）可保护器官和微血管系统免受缺血和再灌注（I/R）的有害影响。最近，我们发现，先前的乙醇摄入引起抗炎表型的发展（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，和白细胞滚动，粘附，并在毛细血管后微静脉的迁移）通过一种新的机制，仍然有效的共存的心血管疾病的危险因素的存在。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）和肿瘤坏死因子-β（TNF）介导的中性粒细胞活化在乙醇暴露期间启动这种适应性转化的重要作用，当组织暴露于乙醇后24小时的I/R时，这种适应性转化在毛细血管后小静脉中变得明显。在目前的提案中，我们试图建立在这些基本观察的基础上，以评估总体假设，即每日适度的EtOH诱导TRPV 1依赖性CGRP从感觉神经元释放，这反过来又激活CD 4 + T淋巴细胞表达肿瘤坏死因子-β（TNF）。肿瘤坏死因子依赖的中性粒细胞蛋白酶介导的信号在血管生成中参与内皮整合素3诱导HO-1表达/活性增加，以限制缺血后微血管功能障碍。为了解决这一假设，我们建议确定的作用：（1）乙醇诱导的，CGRP依赖性激活T淋巴细胞，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，响应于先行乙醇;（2）中性粒细胞蛋白酶启动的、β 3整合素依赖性HO-1表达和活性增加，作为I/R期间观察到的抗炎表型的下游介质。将使用活体显微镜方法定量缺血后白细胞/内皮细胞相互作用。还将研究EtOH升高血浆和组织CGRP和TNF水平、诱导T细胞和中性粒细胞活化以及增加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的作用。重要性：这项工作将确定CGRP激活的T细胞之间的新联系，TNF激活的中性粒细胞的蛋白水解活性产生的信号，和β 3依赖的HO-1表达/活性在获得耐受性I/R的前期乙醇摄入。完成这些研究将为在相关患者人群中开发转化疗法提供机制基础。