Vulnerability to sepsis in old age

老年时容易患败血症

• 批准号: 7415043
• 负责人: Hiroshi Saito
• 金额: $ 21.05万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7415043
• 关键词: Accounting; Affect; Age; Aging; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Cause of Death; Cessation of life; Characteristics; Clinical Trials; Coagulants; Coagulation Process; Doctor of Philosophy; Elderly; Endotoxemia; Endotoxins; Enzymes; Foundations; Functional disorder; Future; Gene Expression; Genes; Goals; Heart; Homeostasis; Incidence; Infection; Inflammation; Inflammatory; Injection of therapeutic agent; Intensive Care Units; Intervention; Intra-abdominal; Kidney; Ligation; Lipopolysaccharides; Liver; Lung; Mediator of activation protein; Messenger RNA; Modeling; Morbidity - disease rate; Multiple Organ Failure; Mus; Mutant Strains Mice; Organ; Oxidative Stress; Patients; Population; Proteins; Puncture procedure; Research; Research Personnel; Risk; Role; Saline; Sepsis; Sepsis Syndrome; Septic Shock; Spleen; Testing; Tissues; age effect; aged; base; improved; innovation; interest; juvenile animal; middle age; mortality; mouse model; novel therapeutics; older patient; research study; response; septic

DESCRIPTION (provided by applicant): Sepsis is an infection-initiated manifestation of the systemic inflammatory response syndrome that often progresses to septic shock, multiple organ failure with high risks of death. Sepsis is a particularly serious problem in the geriatric population, as the elderly patients with sepsis suffer much higher morbidity and mortality than younger patients. In fact, sepsis is a major cause of death in elderly patients at intensive care units in the US. Although this problem is increasingly recognized, the underlying mechanism(s) responsible for this age-associated vulnerability remain largely unknown. The long-term goal of our research is to determine the mechanisms responsible for the increased septic vulnerability in the aged, and to use this information to develop new treatment strategies for sepsis. The age-associated vulnerability to sepsis is also seen in animal models. We have shown that aged mice suffer significantly higher mortality than young mice in two commonly used models for sepsis; endotoxemia induced by bacterial lipopolysaccharide injection, and an intra-abdominal sepsis induced by cecal ligation and puncture. We have also found that the elevated mortality in aged mice is associated with altered inflammatory and coagulation responses, and increased oxidative damages. Our central hypothesis is that loss of homeostasis in old age leads to excessive inflammation, oxidative damage, and coagulation, contributing to the age-associated vulnerability to sepsis. Our objective in this project is to define the age-associated alterations in pathophysiology and gene expression in the mouse model of sepsis, and to develop strategies to improve the survival of the old mice with sepsis. To achieve these goals, we pursue the following three specific aims: (1) To determine the effects of aging on the pathophysiology of sepsis, (2) To identify the age-associated alterations in gene expression that affects mortality in sepsis, and (3) To test likely strategies for their ability to decrease age-associated mortality in sepsis. The information obtained from this project should provide the basis for new therapeutic strategies to substantially decrease the mortality in elderly patients with sepsis.

描述（由申请人提供）： 脓毒症是全身炎症反应综合征的一种感染引发的表现，通常会进展为脓毒性休克、多器官衰竭，并具有高死亡风险。脓毒症在老年人群中是一个特别严重的问题，因为老年脓毒症患者的发病率和死亡率比年轻患者高得多。事实上，败血症是美国重症监护病房老年患者死亡的主要原因。尽管人们越来越认识到这个问题，但造成这种与年龄相关的脆弱性的潜在机制仍然很大程度上未知。我们研究的长期目标是确定导致老年人脓毒症易感性增加的机制，并利用这些信息开发脓毒症的新治疗策略。在动物模型中也发现了与年龄相关的败血症易感性。我们已经证明，在两种常用的脓毒症模型中，老年小鼠的死亡率明显高于年轻小鼠。细菌脂多糖注射引起的内毒素血症，以及盲肠结扎和穿刺引起的腹内败血症。我们还发现，老年小鼠死亡率升高与炎症和凝血反应的改变以及氧化损伤的增加有关。我们的中心假设是，老年时体内平衡的丧失会导致过度炎症、氧化损伤和凝血，从而导致与年龄相关的败血症的脆弱性。我们在这个项目中的目标是确定败血症小鼠模型中与年龄相关的病理生理学和基因表达的变化，并制定提高败血症老年小鼠存活率的策略。为了实现这些目标，我们追求以下三个具体目标：（1）确定衰老对脓毒症病理生理学的影响，（2）确定影响脓毒症死亡率的与年龄相关的基因表达变化，以及（3） ）测试可能的策略是否能够降低脓毒症中与年龄相关的死亡率。从该项目获得的信息应该为新的治疗策略提供基础，以大幅降低老年脓毒症患者的死亡率。