Effect of nicotine on postischemic brain inflammation.

尼古丁对缺血后脑炎症的影响。

• 批准号: 7587078
• 负责人: ANUSKA V. ANDJELKOVIC-ZOCHOWSKA
• 金额: $ 20.19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-20 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587078
• 关键词: Adhesions; Affect; Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Ischemia; CCL2 gene; CX3C Chemokines; CX3CL1 gene; CXC Chemokines; CXCL5 gene; Cell Adhesion Molecules; Cell Communication; Cells; Central Nervous System Diseases; Cerebrovascular Circulation; Cerebrum; Chemotactic Factors; Chronic; Condition; Coronary artery; Cotinine; Data; Disruption; Encephalitis; Endothelial Cells; Endothelium; Exposure to; Fractalkine; Glucose; Goals; Human; IL8 gene; ITGB2 gene; Immune response; In Vitro; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Intercellular adhesion molecule 1; Ischemia; Kidney; Lead; Leukocyte Rolling; Leukocytes; Liver; Mediating; Mediator of activation protein; Messenger RNA; Middle Cerebral Artery Occlusion; Molecular; Mus; Neuroglia; Neurologic; Neurons; Nicotine; Nicotinic Receptors; Outcome; Oxygen; P-Selectin; Pathway interactions; Peripheral; Phenotype; Physiological reperfusion; Play; Process; Proteins; Public Health; Purpose; Rate; Reaction; Recovery; Reperfusion Injury; Reperfusion Therapy; Research; Rho-associated kinase; Risk Factors; Role; Signal Pathway; Signal Transduction; Smoker; Stimulus; Stroke; Testing; Therapeutic; Thrombus; Time; Traumatic Brain Injury; Umbilical vein; Up-Regulation; base; beta-Chemokines; cerebrovascular; chemokine; cigarette smoking; cytokine; day; deprivation; design; enhancing factor; human CXCL5 protein; in vitro Model; in vivo; insight; migration; modifiable risk; monocyte; mortality; mouse model; neutrophil; protein expression; receptor; relating to nervous system; research study; rho; size; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): A substantial body of evidence suggests that nicotine adversely affects cerebral blood flow and peripheral thrombus formation by inducing breakdown of the blood-brain barrier and alterations in the cerebrovascular endothelium. Some of the alterations in brain endothelial phenotype and function are denoted as proinflammatory, indicating that nicotine may regulate expression of some proinflammatory mediators such as cytokines and adhesion molecules. Our preliminary data support this observation and indicate that chronic exposure to nicotine (14 days) has a profound effect on postischemic injury (2-fold increase in infarct size) and on the progression of the inflammatory response. Particularly, administration of nicotine markedly increased leukocyte migration into postischemic mouse brain and also induced high expression of chemokine CCL2. That chemokine is a major factor orchestrating the immune response and it plays a pivotal role in leukocyte recruitment during postichemic inflammation. To further explore this issue, we propose a research plan directed to test the hypothesis: "Nicotine augments postischemic inflammatory response in the brain by inducing a prolonged increase in expression of chemokines." Specifically, we will determine whether nicotine and/or cotonine exposure can induce or maintain the inflammatory response of brain endothelial cells through the stimulation of CCL2 expression in these cells under in vitro and in vivo basal (i.e., normal oxygen and glucose supply) and ischemia/reperfusion (I/R) conditions (specific aim 1) and to establish the components of the signaling pathway (transcription factor NF:B and Rho/Rho kinase pathway) that underlie the upregulation of CCL2 expression in mouse brain endothelial cells by nicotine during postischemic injury (specific aim 2). To accomplish our goal, we will conduct both in vitro and in vivo experiments. For in vitro experiments, brain microvessel endothelial cell cultures will be subjected to combined oxygen glucose deprivation followed by recovery (in vitro model of I/R). In vivo experiments will be performed on a mouse model of brain I/R injury (transient middle cerebral artery occlusion). Collectively, these experiments will serve to illuminate, for the first time, how nicotine can regulate postischemic inflammatory response. PUBLIC HEALTH RELEVANCE: Cigarette smoking is widely recognized as a major modifiable risk factor for stroke and it is causally associated with a worse stroke outcome. The purpose of this study is to provide a better understanding of the relationship between cigarette smoking and stroke and this may lead to the design of a rational therapeutic approach to stroke in smokers.

描述（由申请人提供）：大量证据表明，尼古丁通过诱导血脑屏障的破坏和脑血管内皮的改变，对脑血流和外周血栓形成产生不利影响。脑内皮表型和功能的一些改变被认为是促炎性的，表明尼古丁可能调节一些促炎性介质的表达，例如细胞因子和粘附分子。我们的初步数据支持这一观察结果，并表明长期接触尼古丁（14 天）对缺血后损伤（梗死面积增加 2 倍）和炎症反应的进展具有深远影响。特别是，尼古丁的施用显着增加了白细胞向缺血后小鼠大脑的迁移，并且还诱导了趋化因子CCL2的高表达。该趋化因子是协调免疫反应的主要因素，在缺血后炎症期间的白细胞募集中发挥着关键作用。为了进一步探讨这个问题，我们提出了一项研究计划，旨在检验以下假设：“尼古丁通过诱导趋化因子表达的长期增加来增强大脑的缺血后炎症反应。”具体来说，我们将确定在体外和体内基础（即正常的氧和葡萄糖供应）和缺血条件下，尼古丁和/或可托宁暴露是否可以通过刺激这些细胞中的CCL2表达来诱导或维持脑内皮细胞的炎症反应。 /再灌注 (I/R) 条件（具体目标 1）并建立信号通路的组成部分（转录因子 NF:B 和 Rho/Rho 激酶通路），这些通路是上调缺血后损伤期间尼古丁在小鼠脑内皮细胞中表达 CCL2（具体目标 2）。为了实现我们的目标，我们将进行体外和体内实验。对于体外实验，脑微血管内皮细胞培养物将接受联合缺氧葡萄糖剥夺，然后恢复（I/R 体外模型）。体内实验将在小鼠脑 I/R 损伤模型（短暂的大脑中动脉闭塞）上进行。总的来说，这些实验将首次阐明尼古丁如何调节缺血后炎症反应。公众健康相关性：吸烟被广泛认为是中风的一个主要的可改变危险因素，并且与更差的中风结果存在因果关系。本研究的目的是为了更好地了解吸烟与中风之间的关系，这可能有助于设计合理的吸烟者中风治疗方法。