Vulnerability to sepsis in old age

描述(由申请人提供)： 脓毒症是感染引发的全身炎症反应综合征的表现，通常进展为感染性休克，即多器官衰竭，死亡风险很高。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一问题，但造成这种与年龄相关的脆弱性的潜在机制(S)在很大程度上仍不清楚。我们研究的长期目标是确定导致老年人败血症易感性增加的机制，并利用这些信息开发新的脓毒症治疗策略。在动物模型中也可以看到与年龄相关的败血症易感性。我们发现，在两种常用的脓毒症模型中，老年小鼠的死亡率显著高于年轻小鼠：细菌脂多糖注射诱导的内毒素血症，以及盲肠结扎和穿孔诱导的腹内败血症。我们还发现，老年小鼠死亡率的增加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，老年人体内平衡的丧失会导致过度的炎症、氧化损伤和凝血，导致与年龄相关的败血症易感性。我们在这个项目中的目标是确定脓毒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，并开发提高老年脓毒症小鼠存活率的策略。为了实现这些目标，我们追求以下三个具体目标：(1)确定衰老对脓毒症的病理生理学的影响，(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)测试它们降低脓毒症年龄相关死亡率的可能策略。从这个项目中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。

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.