Accelerated Biologic Aging and Risk for Sepsis and Organ Failure Following Trauma

加速生物衰老以及创伤后败血症和器官衰竭的风险

• 批准号: 8118557
• 负责人: ELIZABETH Grooms NESMITH
• 金额: $ 9.37万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118557
• 关键词: Accident and Emergency department; Acute; Address; Admission activity; Adrenal Cortex Hormones; Adrenal Glands; Affect; African American; Aging; Autoimmune Process; Basic Science; Behavioral; Behavioral Mechanisms; Biological Markers; Blood Transfusion; Caucasians; Caucasoid Race; Cause of Death; Cell Death; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic stress; Clinical Sciences; Critical Care; Data; Demographic Factors; Development; Disease; Elderly; Equilibrium; Event; Fatal Outcome; Feedback; Functional disorder; Future; Genetic; Glucocorticoids; Goals; Hair; Hormones; Hospitals; Hour; Hydrocortisone; Immune System Diseases; Immune system; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury Severity Score; Intensive Care Units; Knowledge; Lead; Length of Stay; Life; Link; Malignant Neoplasms; Measures; Mission; Morbidity - disease rate; Mutation; National Institute of Nursing Research; Non-Steroidal Anti-Inflammatory Agents; Organ; Organ failure; Outcome; Participant; Pathway interactions; Patients; Persons; Physiological; Plasma; Population; Predisposing Factor; Predisposition; Pregnancy; Premature aging syndrome; Prevention; Psychoneuroimmunology; Race; Recruitment Activity; Reporting; Research; Research Proposals; Research Support; Research Training; Risk; Risk Factors; Schedule; Science; Sepsis; Socioeconomic Status; Spinal cord injury; Steroids; Stress; System; Telomerase; Time; Trauma; United States National Institutes of Health; Vulnerable Populations; aged; allostatic load; base; career; cytokine; disorder prevention; immune function; killings; lifestyle factors; low socioeconomic status; mortality; neutrophil; premature; prevent; primary outcome; public health relevance; response; salicylate; statistics; symposium

DESCRIPTION (provided by applicant): Guided by an adapted version of the Vulnerable Populations Conceptual Framework which incorporates concepts from Psychoneuroimmunology, this project will examine bio-behavioral mechanisms associated with chronic stress and accelerated biologic aging (i.e. premature cell death and system decline) which could adversely affect susceptibility to sepsis and organ failure following trauma (i.e., acute, life-threatening injuries). Trauma kills more than 13 million people annually. Sepsis and organ failure are the leading causes of in- hospital trauma deaths and are affected by baseline inflammation and poor inflammatory response, yet few data exist to explain differences in vulnerability to these deadly outcomes. Research has shown that African Americans (AAs) and persons of low socioeconomic status (SES) have nearly twice the rates of sepsis and organ dysfunction as Caucasians. Low SES has been associated with baseline inflammation, a finding related to organ dysfunction. Chronic stress may be a contributing factor. AAs and persons of low SES report chronic stress, which has been linked to accelerated biologic aging via telomerase activity. Declining levels of telomerase have also been associated with advanced age, a known risk factor for sepsis and organ failure. Chronic stress has been linked with physiologic "wear and tear" (i.e. allostatic load) on immune system function, resulting in changes similar that which are seen with advanced age. Thus, the specific aims of this project are that 1) accelerated biologic aging is a significant predisposing factor contributing to susceptibility to sepsis and organ failure following trauma and 2) chronic stress is a significant predisposing factor contributing to increased baseline inflammation and differences in the magnitude of the inflammatory response. Trauma patients who are 1) 18-44 years old; 2) have injury severity scores >15; and 3) times of <1 hour from injury to Emergency Department admission (n =300) will be recruited. Accelerated biologic aging will be operationally defined by low telomerase activity. Chronic stress will be operationally defined by high scores on the Life Events and Difficulties Schedule and high hair cortisol. Participants will be excluded for 1) blood transfusion or infection < 2 weeks prior to admission; 2) steroid, NSAID, or salicylate use for > 1 month prior to admission; 3) pre-existing organ disease; 4) cancer, autoimmune conditions, or pregnancy; 5) spinal cord injury; or missing data. Primary outcome variables are susceptibility to sepsis and organ failure, baseline inflammation status, and magnitude of the inflammatory response to trauma indicated by the 1) overall response and 2) peak magnitude of inflammatory cytokines and immature neutrophils in plasma from ED admission through ICU length of stay. Secondary variables will also be analyzed, including socio-demographic and lifestyle factors. Knowledge gained will inform future studies to prevent these often-fatal outcomes. This research is consistent with the National Institute of Nursing Research mission, which supports research that incorporates the best of clinical and basic science to develop unique approaches to disease prevention. PUBLIC HEALTH RELEVANCE: Trauma, defined as acute, life-threatening injuries, is the leading cause of death for individuals aged 18-44 years. Accelerated (i.e., premature) aging and chronic stress before trauma could explain why some individuals have poor outcomes in the intensive care unit after trauma, such as sepsis and organ failure. Information from this research will help us better understand why different populations of trauma patients have different outcomes, and could be used in future studies aimed at prevention.

描述(由申请人提供)：在纳入心理神经免疫学概念的脆弱人群概念框架的改编版本的指导下，该项目将研究与慢性应激和加速的生物衰老(即细胞过早死亡和系统衰退)相关的生物行为机制，这些机制可能对创伤(即急性、危及生命的伤害)后的脓毒症和器官衰竭的易感性产生不利影响。创伤每年导致1300多万人死亡。脓毒症和器官衰竭是院内创伤死亡的主要原因，受基线炎症和炎症反应不良的影响，但几乎没有数据来解释这些致命后果的易感性差异。研究表明，非裔美国人(AAs)和社会经济地位较低的人(SES)的脓毒症和器官功能障碍的发生率几乎是高加索人的两倍。低SES与基线炎症有关，这一发现与器官功能障碍有关。慢性压力可能是一个促成因素。AAS和SES低的人报告了慢性应激，这与通过端粒酶活性加速生物衰老有关。端粒酶水平的下降也与高龄有关，高龄是败血症和器官衰竭的已知风险因素。慢性应激与免疫系统功能的生理“磨损”(即稳态负荷)有关，导致的变化与老年相似。因此，该项目的具体目标是：1)加速的生物衰老是导致创伤后脓毒症和器官衰竭易感性的重要易感因素；2)慢性应激是导致基线炎症增加和炎症反应程度差异的重要易感因素。创伤患者年龄1)18-44岁；2)创伤严重程度评分<15；3)从受伤到急诊科入院时间<1；1小时(n=300)。加速的生物衰老将在操作上被定义为低端粒酶活性。慢性压力将被定义为生活事件和困难时间表上的高分和高皮质醇。参与者将被排除在1)入院前2周内输血或感染；2)入院前1个月使用类固醇、非甾体抗炎药或水杨酸盐；3)既往存在的器官疾病；4)癌症、自身免疫性疾病或怀孕；5)脊髓损伤；或数据缺失。主要结果变量是败血症和器官衰竭的易感性、基线炎症状态和创伤炎症反应的大小，由1)总体反应和2)从ED入院到ICU住院期间血浆中炎性细胞因子和未成熟中性粒细胞的峰值大小来指示。还将分析次要变量，包括社会人口和生活方式因素。所获得的知识将为未来的研究提供依据，以防止这些往往致命的结果。这项研究与国家护理研究所的使命是一致的，该使命支持结合最好的临床和基础科学的研究，以开发独特的疾病预防方法。 公共卫生相关性：创伤被定义为急性、危及生命的伤害，是18-44岁人群的主要死亡原因。创伤前加速(即过早)衰老和慢性应激可以解释为什么一些人在创伤后在重症监护病房结果不佳，如败血症和器官衰竭。这项研究的信息将帮助我们更好地理解为什么不同人群的创伤患者会有不同的结果，并可用于未来旨在预防的研究中。