Stress Impaired Microbial Clearance

压力损害微生物清除

• 批准号: 7568850
• 负责人: PHILLIP T. MARUCHA
• 金额: $ 38.07万
• 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/7568850
• 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; Hypothalamic structure; Hypoxia; Immune system; Infection; Interleukin-1; Left; Life; Mediator of activation protein; Modeling; Mus; Operative Surgical Procedures; Outcome; Oxidants; Oxygen; Pathway interactions; Patients; Peripheral; Phagocytes; Phagocytosis; Pituitary Gland; 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，从而使宿主处于感染的危险之中。2-20%的手术患者发生感染（Samson 2004），这取决于手术部位。平均而言，感染使病人住院时间增加10.2天（Zoutman 1998年），治疗费用增加17 708美元（Whitehouse 2002年）。心理压力已被证明可以延缓人类和动物的伤口愈合。此外，应激小鼠的实验伤口所含的细菌比对照小鼠的伤口多4倍（Rojas et al., 2002），表明微生物清除能力减弱。两个通路可能是重要的，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，这是已知的抑制免疫系统的物质。在这个模型中，SNS的主要作用似乎是血管收缩，导致向组织的氧气输送受损。氧气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。本提案的目的是确定应激损害微生物清除的机制，使用一个特征良好的，自然的伤口感染模型，并开始开发方法来改善和恢复这些影响。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)表征应激对伤口愈合过程中自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损伤微生物清除中的相对/联合作用；3)确定氧在愈合过程中应激损伤微生物清除中的作用。压力是我们日常生活的一部分，已经证明，从学术考试到照顾阿尔茨海默病患者的活动分别导致40%和24%的伤口愈合延迟（Marucha et al. 1998; Kiecolt-Glaser, Marucha et al. 1995，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。