Stress Impaired Microbial Clearance

压力损害微生物清除

• 批准号: 8033110
• 负责人: PHILLIP T. MARUCHA
• 金额: $ 36.56万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033110
• 关键词: Adrenal Glands; Adrenergic Antagonists; Alzheimer' s Disease; Animal Model; Animals; Bacteria; Blood Vessels; Blood flow; Cells; Chemotaxis; Data; Electron Spin Resonance Spectroscopy; Epinephrine; Gene Expression; Genes; Glucocorticoids; Goals; Growth Factor; Healed; Hospitalization; Human; Hydrogen Peroxide; Hyperbaric Oxygen; Hypoxia; Immune system; Infection; Interleukin-1; Left; Mediator of activation protein; Modeling; Mus; Operative Surgical Procedures; Outcome; Oxidants; Oxygen; Pathway interactions; Patients; Peripheral; Phagocytes; Phagocytosis; Play; Production; Psychological Stress; RU-486; Reactive Oxygen Species; Relative (related person); Respiratory Burst; Risk; Role; Site; Stress; Superoxides; Sympathetic Nervous System; System; Time; Tissues; Treatment Cost; Wound Healing; antimicrobial; base; caregiving; chemokine; clinically relevant; cytokine; effective intervention; healing; hypothalamic-pituitary-adrenal axis; improved; macrophage; microbial; mouse model; neutrophil; new technology; restoration; restraint; restraint stress; stressor; transcription factor; vasoconstriction; wound

DESCRIPTION (provided by applicant): Psychological stress has been shown to compromise several components of the natural immune system that can leave the host at risk for infection. Infections occur in 2-20% of surgery patients (Samson 2004) depending on the site. On average, infection increases the patient's hospitalization time by 10.2 days (Zoutman 1998) and the cost of treatment by $17,708 (Whitehouse 2002). Psychological stress has been shown to delay wound closure in humans and animals. Also, experimental wounds placed in stressed mice contain greater than 4 logs more bacteria than wounds of control mice (Rojas et al., 2002), demonstrating weakened microbial clearance. Two pathways are likely to be important, the hypothalamic pituitary adrenal axis (HPA) and the sympathetic nervous system (SNS). Activation of the HPA axis results in the release of glucocorticoids and epinephrine, which are known to inhibit the immune system. The SNS in this model appears to have its main effect on vasoconstriction of blood vessels leading to impaired oxygen delivery to the tissue. Oxygen is critical to microbial clearance and therefore is likely to play an important role in stress-impaired microbial clearance. The objective of this proposal is to determine the mechanisms by which stress impairs microbial clearance using a well-characterized, naturalistic wound model of infection and to begin to develop approaches to improve and restore these effects. We will also verify our finding in a clinically relevant incisional model. The specific aims of this study are to: 1) characterize the effects of stress on the role of the natural immune system during wound healing, 2) determine the relative/combined roles of the HPA axis and sympathetic nervous system in stress impaired microbial clearance, and 3) determine the role of oxygen on stress-impaired microbial clearance during healing. Stress is a component of our everyday lives and it has been proven that activities from academic examinations to care giving for Alzheimer's patients result in delayed wound closure by 40% and 24% respectively (Marucha et al. 1998; Kiecolt-Glaser, Marucha et al. 1995, see appendix). The goal of this project is to identify the mechanisms which underlie stress-impaired microbial clearance and ultimately develop appropriate therapy.

描述(由申请人提供)：心理压力已被证明会损害自然免疫系统的几个组成部分，可能会使宿主处于感染的风险中。感染发生在2-20%的手术患者(Samson，2004年)，具体取决于不同的部位。平均而言，感染使患者的住院时间增加了10.2天(Zoutman 1998)，治疗费用增加了17,708美元(Whitehouse 2002)。心理压力已被证明会推迟人类和动物的伤口闭合。此外，放置在应激小鼠身上的实验伤口比对照小鼠伤口含有的细菌多4个对数(Rojas等人，2002年)，表明微生物清除能力减弱。有两条通路可能很重要，即下丘脑-垂体-肾上腺轴(HPA)和交感神经系统(SNS)。HPA轴的激活会导致糖皮质激素和肾上腺素的释放，这是已知的抑制免疫系统的物质。在这个模型中，SNS似乎对血管收缩有主要作用，导致组织氧输送受损。氧对微生物的清除至关重要，因此很可能在应激损伤的微生物清除中发挥重要作用。这项建议的目的是利用一种具有良好特征的、自然的伤口感染模型来确定应激损害微生物清除的机制，并开始开发改善和恢复这些影响的方法。我们还将在临床相关的切开模型中验证我们的发现。本研究的具体目的是：1)确定应激对自然免疫系统在创伤愈合过程中的作用的影响；2)确定HPA轴和交感神经系统在应激损害的微生物清除中的相对/联合作用；3)确定氧在应激损害的愈合过程中对微生物清除的作用。压力是我们日常生活的一个组成部分，事实证明，从学术考试到照顾阿尔茨海默氏症患者的活动分别导致伤口延迟愈合40%和24%(Marucha等人)。1998年；Kiecolt-Gaser，Marucha等人。1995年，见附录)。该项目的目标是确定压力损害微生物清除的机制，并最终开发适当的治疗方法。