Stress Impaired Microbial Clearance

描述（由申请人提供）：心理压力已被证明会损害天然免疫系统的几个组成部分，从而使宿主处于感染风险中。2-20%的手术患者发生感染（Samson 2004），具体取决于手术部位。平均而言，感染使患者的住院时间增加10.2天（Zoutman 1998），治疗费用增加17，708美元（怀特豪斯2002）。心理压力已被证明会延迟人类和动物的伤口闭合。此外，置于应激小鼠中的实验伤口比对照小鼠的伤口含有多于4个对数的细菌（Rojas等人，2002年），证明微生物清除减弱。两个途径可能是重要的，下丘脑垂体肾上腺轴（HPA）和交感神经系统（SNS）。HPA轴的激活导致糖皮质激素和肾上腺素的释放，已知其抑制免疫系统。该模型中的SNS似乎对血管的血管收缩具有其主要作用，导致向组织的氧递送受损。氧对微生物清除至关重要，因此可能在应激受损的微生物清除中发挥重要作用。本提案的目的是使用充分表征的自然伤口感染模型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效应的方法。我们还将在临床相关的切口模型中验证我们的发现。本研究的具体目的是：1）表征创伤愈合期间应激对天然免疫系统作用的影响，2）确定HPA轴和交感神经系统在应激受损微生物清除中的相对/组合作用，以及3）确定愈合期间氧对应激受损微生物清除的作用。压力是我们日常生活的组成部分，已经证明，从学术考试到为阿尔茨海默病患者提供护理的活动分别导致40%和24%的伤口闭合延迟（Marucha等人，1998年; Kiecolt-Glaser，Marucha等人，1995年，见附录）。该项目的目标是确定压力受损的微生物清除的机制，并最终开发适当的治疗方法。

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.