Mechanisms Mediating Hypotension to Anthrax Lethal Toxin

炭疽致死毒素介导低血压的机制

• 批准号: 7750596
• 负责人: Michael J Kenney
• 金额: $ 22.2万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750596
• 关键词: Acute; Address; Adrenal Medulla; Adrenergic Agents; Adrenergic Receptor; Anthrax disease; Antihypertensive Agents; Bacillus anthracis; Bioterrorism; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cardiac Output; Cardiovascular alteration; Cardiovascular system; Chronic; Continuous Infusion; Depressed mood; Edema; Endothelium; Epinephrine; Health; Heart; Hypotension; Hypoxemia; Infection; Inflammatory; Infusion procedures; Injury; Left Ventricular Function; Link; Measurement; Mediating; Mental Depression; Modeling; Myocardial; Nerve; Neurologic; Neurons; Nitric Oxide; Norepinephrine; Pathogenesis; Patients; Peripheral; Phenotype; Play; Production; Rattus; Regulation; Reporting; Research Design; Research Personnel; Resistance; Respiratory physiology; Role; Serum; Shock; Source; Sympathetic Nervous System; System; Time; Toxin; United States; United States National Institutes of Health; Vascular resistance; Vasoconstrictor Agents; Vasodilation; Visceral; adrenergic; anthrax lethal factor; blood pressure regulation; controlled release; conventional therapy; cytokine; improved; neural circuit; neurotransmitter release; noradrenergic; peripheral blood; public health relevance; response; stressor; therapy development

DESCRIPTION (provided by applicant): Bacillus anthracis infection is a deadly pathophysiological condition and a major bioterrorism health threat. The treatment of patients infected with inhalational Bacillus anthracis in the United States was complicated by progressive decreases in arterial blood pressure. To investigate the pathogenesis of the shock-like reduction in arterial blood pressure with Bacillus anthracis, investigators at the National Institutes of Health developed a rat model using continuous infusions of anthrax lethal toxin (LeTx) and anthrax edema toxin (ETx) (these toxins are central to the pathogenesis of Bacillus anthracis). These investigators reported that LeTx and ETx infusions produced hypotension; however, mechanisms mediating the depression in arterial blood pressure are not known. Although neurological complications are a fundamental component of Bacillus anthracis infections, no studies have determined the effect of Bacillus anthracis infection on sympathetic nerve outflow, the fundamental link between central sympathetic neural circuits and regulation of cardiac output, vascular resistance, and arterial blood pressure. The proposed studies will, for the first time, advance the hypothesis that Bacillus anthracis infection mediates progressive hypotension by altering regulation of sympathetic nerve outflow, cardiac output, vascular reactivity, and peripheral vascular conductance. An integrative and multifaceted experimental approach involving sympathetic nerve, cardiac output, left ventricular function, alpha-adrenergic vasoconstrictor, endothelium-dependent and -independent vasodilation, and regional vascular conductance measurements to continuous LeTx, ETx, and combined LeTx+ETx infusions will be completed in rats to address four questions. 1. Does infusion of Bacillus anthracis toxins produce sympathoinhibition? 2. Is cardiac function depressed in response to infusion of Bacillus anthracis toxins? 3. Do infusions of Bacillus anthracis toxins reduce 11-adrenergic receptor vascular responsiveness and alter endothelium-dependent and - independent vasodilation? 4. Is the distribution of visceral and peripheral blood flow altered by infusion of Bacillus anthracis toxins? The elaboration of mechanisms mediating hypotension to LeTx and ETx infusions is important for determining the efficacy of conventional therapy and the development of improved therapies in response to Bacillus anthracis infection. PUBLIC HEALTH RELEVANCE: Bacillus anthracis infection is a deadly pathophysiological state and a serious bioterrorism health threat. The proposed studies are designed to determine sympathetic nervous system and cardiovascular mechanisms responsible for the reduction in arterial blood pressure during infusion of anthrax lethal toxin. Further understanding of the mechanisms mediating sympathetic nerve and cardiovascular alterations to anthrax lethal toxin is critical for determining the efficacy of conventional therapy and the development of improved therapies for Bacillus anthracis infection.

描述（由申请人提供）：炭疽杆菌感染是一种致命的病理生理疾病，是一种重大的生物恐怖主义健康威胁。在美国，吸入性炭疽杆菌感染患者的治疗伴有进行性血压下降。为了研究炭疽芽孢杆菌引起的休克样动脉血压降低的发病机制，美国国立卫生研究院的研究人员开发了一种大鼠模型，使用连续输注炭疽致死毒素（LeTx）和炭疽水肿毒素（ETx）（这些毒素是炭疽芽孢杆菌发病机制的核心）。这些研究者报告LeTx和ETx输注产生低血压；然而，调节动脉血压下降的机制尚不清楚。虽然神经系统并发症是炭疽芽孢杆菌感染的基本组成部分，但没有研究确定炭疽芽孢杆菌感染对交感神经流出的影响，而交感神经中枢回路与心输出量、血管阻力和动脉血压调节之间的基本联系。提出的研究将首次提出炭疽杆菌感染通过改变交感神经外流、心输出量、血管反应性和周围血管传导调节介导进行性低血压的假设。为了解决四个问题，我们将在大鼠中完成一个综合的、多方面的实验方法，包括交感神经、心输出量、左心室功能、α -肾上腺素能血管收缩剂、内皮依赖性和非依赖性血管舒张以及局部血管电导测量，以连续注射LeTx、ETx和LeTx+ETx。1. 输注炭疽杆菌毒素是否产生交感神经抑制？2. 注射炭疽芽孢杆菌毒素是否会抑制心功能？3. 炭疽芽孢杆菌毒素是否会降低11-肾上腺素受体血管反应性并改变内皮依赖性和非依赖性血管舒张？4. 注射炭疽杆菌毒素会改变内脏和外周血流量的分布吗？阐明LeTx和ETx输注导致低血压的机制对于确定常规治疗的疗效和开发针对炭疽芽孢杆菌感染的改进治疗具有重要意义。公共卫生相关性：炭疽芽孢杆菌感染是一种致命的病理生理状态和严重的生物恐怖主义健康威胁。所提出的研究旨在确定交感神经系统和心血管机制负责降低动脉血压在输注炭疽致死毒素。进一步了解交感神经和心血管对炭疽致死毒素改变的机制对于确定常规治疗的疗效和开发改进的炭疽芽孢杆菌感染治疗方法至关重要。

项目成果

Bacillus anthracis lethal toxin induces complex changes in sympathetic nerve discharge regulation.

• DOI: 10.1016/j.autneu.2012.06.007
• 发表时间: 2012-09-25
• 期刊: AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL
• 影响因子: 2.7
• 作者: Kenney, M. J.;Mosher, L. J.;Fels, R. J.
• 通讯作者: Fels, R. J.

Is visceral sympathoexcitation to heat stress dependent on activation of ionotropic excitatory amino acid receptors in the rostral ventrolateral medulla?

• DOI: 10.1152/ajpregu.00113.2011
• 发表时间: 2011-08-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
• 影响因子: 2.8
• 作者: Kenney, M. J.;Meyer, C. N.;Fels, R. J.
• 通讯作者: Fels, R. J.