Hormone and Cytokine Regulation of Endotoxin Injury

内毒素损伤的激素和细胞因子调节

基本信息

批准号：
8328874
负责人：
SIOBHAN A CORBETT
金额：
$ 21万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-04-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8328874
关键词：
Acute Adult Agonist Anti-Inflammatory Agents Anti-inflammatory Attenuated Autonomic Dysfunction Autonomic Pathways Biology Catecholamines Cholinergic Receptors Clinical Critical Care Critical Illness Data Distant Effectiveness Endocrine Endotoxins Equilibrium Event Exhibits Fatty acid glycerol esters Functional disorder Funding Glucocorticoids Hormonal Hormones Hospitalization Hour Human Hydrocortisone Immune Immune response Incidence Infection Inflammation Inflammatory Inflammatory Response Infusion procedures Injury Intervention Intestines Lead Limb structure Mediating Modeling Morbidity - disease rate Nerve Nutrient Operative Surgical Procedures Organ Organ failure Parenteral Nutrition Pathway interactions Patients Peripheral Public Health Recovery Regulation Research Personnel Risk Role Secondary to Signal Transduction Solid Sterility Stimulus Stress Testing Therapeutic Time Tissues Trauma Vagus nerve structure adverse outcome cholinergic clinically significant cytokine deprivation heart rate variability in vivo injured mortality programs response stressor trafficking

项目摘要

DESCRIPTION (provided by applicant): Severe injury and infection are leading causes of morbidity and mortality among adults. Such severe conditions evoke both pro-inflammatory and anti-inflammatory responses at the systemic and tissue levels. While systemic anti-inflammation is directed initially by hormonal and autonomic influences, the effectiveness of these systemic anti-inflammatory mechanisms dissipates during prolonged stressful conditions. In the context of a subsequent (e.g. infectious) challenge, alternative anti-inflammatory pathway(s) must compensate for the diminished regulatory influences exerted by endocrine hormones, such as cortisol and catecholamines. In the current proposal, we hypothesize that competent vagal autonomic pathways assume greater significance for dampening inflammatory stress during prolonged recovery. In modeling the human reponse to initially sterile (hormone infusion) and subsequent inflammatory (endotoxinemia) stressors, we have noted a diminution of endocrine mediated anti-inflammatory responsiveness. Hence, we propose that any acquired vagal autonomic dysfunction (VAD) becomes a limiting factor for dampening pro-inflammatory responses to secondary stressful stimulus, such as endotoxin. In Specifc Aim #1, we will A) model a period of sterile stress (via stress hormone infusion) to ascertain the role of vagal autonomic function (by heart rate variability determinations) upon endotoxin-induced systemic pro- and anti-inflammatory responses in humans. We also will, B) utilize an agonist of the vagal cholinergic anti-inflammatory pathway to ascertain the influence of this agent upon inflammatory responses to endotoxin following a period of hormone stress. We have recently documented acquired VAD during intestinal nutrient deprivation. In Specifc Aim #2, we will utilize this human model to ascertain acute intestinal nutrient (high-fat) stimulation on vagal tone and the response to endotoxin. In Specific Aim #3, we will determine the incidence and consequences of sterile stress (trauma and surgery) induced alterations of inflammatory balance and VAD in critically-ill patients at risk for a secondary stimulus, such as infection and/or organ failure. Relevance to Public Health: The proposed studies will clarify the clinical contexts in which vagal autonomic dysfunction contributes to morbidity and mortality in severely stressed patients. The proposed low-risk interventions will also define opportunities to enhance vagally regulated anti-inflammatory responses.

描述（由申请人提供）：严重伤害和感染是成年人发病和死亡率的主要原因。这种严重的条件引起了全身和组织水平上的促炎和抗炎反应。尽管最初是由荷尔蒙和自主性影响指导的全身性抗炎，但这些全身性抗炎机制的有效性在长期的压力条件下消散了。在随后的（例如传染性）挑战的背景下，替代性抗炎途径必须弥补内分泌激素（例如皮质醇和儿童胺）所施加的调节性影响减少。在当前的提案中，我们假设有能力的迷走神经自主神经途径对长期恢复过程中炎症压力的抑制作用具有更大的意义。在建模人类对最初无菌（激素输注）和随后的炎症（内毒素血症）应激源的响应时，我们注意到内分泌介导的抗炎反应性的减少。因此，我们建议任何获得的迷走神经自主神经功能障碍（VAD）成为抑制对继发性压力刺激（例如内毒素）促炎反应的限制因素。在指定目标＃1中，我们将a）模拟一个无菌应力时期（通过压力激素输注），以确定迷走神经自主神经功能（通过心率可变性确定）对内毒素诱导的人类系统性和抗炎反应的作用。 b）我们还将利用迷走神经能抗炎途径的激动剂来确定该药物对激素胁迫后对内毒素的炎症反应的影响。我们最近记录了在肠道营养剥夺期间获得的VAD。在指定目标＃2中，我们将利用这种人类模型来确定迷走神经张力的急性肠道营养（高脂）刺激和对内毒素的反应。在特定的目标＃3中，我们将确定无菌应激（创伤和手术）的发病率和后果诱导的炎症平衡和VAD的改变，对有继发性刺激的风险，例如感染和/或器官衰竭。与公共卫生的相关性：拟议的研究将阐明迷走神经自主神经功能障碍有助于严重压力患者的发病率和死亡率的临床环境。拟议的低风险干预措施还将定义机会，以增强模糊调节的抗炎反应。

项目成果

期刊论文数量（156）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

IL-8 in septic shock, endotoxemia, and after IL-1 administration.

DOI：
10.4049/jimmunol.146.10.3478
发表时间：
1991-05
期刊：
Journal of immunology
影响因子：
4.4
作者：
K. Zee;L. Deforge;E. Fischer;M. Marano;J. Kenney;D. Remick;S. Lowry;L. Moldawer
通讯作者：
K. Zee;L. Deforge;E. Fischer;M. Marano;J. Kenney;D. Remick;S. Lowry;L. Moldawer

Interleukin-1 contributes to increased concentrations of soluble tumor necrosis factor receptor type I in sepsis.

在脓毒症中，IL-1 有助于增加 I 型可溶性肿瘤坏死因子受体的浓度。

DOI：
10.1093/infdis/172.2.577
发表时间：
1995
期刊：
The Journal of infectious diseases
影响因子：
0
作者：
vanderPoll,T;Fischer,E;Coyle,SM;VanZee,KJ;Pribble,JP;Stiles,DM;Barie,PS;Buurman,WA;Moldawer,LL;Lowry,SF
通讯作者：
Lowry,SF

Translational applications of evaluating physiologic variability in human endotoxemia.

DOI：
10.1007/s10877-012-9418-1
发表时间：
2013-08
期刊：
JOURNAL OF CLINICAL MONITORING AND COMPUTING
影响因子：
2.2
作者：
Scheff, Jeremy D.;Mavroudis, Panteleimon D.;Calvano, Steve E.;Androulakis, Ioannis P.
通讯作者：
Androulakis, Ioannis P.

Thermogenic and nitrogen response to submaximal exercise in parenterally repleted normal man.

正常人肠胃外补充后对次最大运动的生热和氮反应。