Vulnerability to sepsis in old age

描述（由申请人提供）： 脓毒症是由感染引发的全身炎症反应综合征的一种表现，常发展为脓毒性休克、多器官功能衰竭，死亡风险高。脓毒症是老年人群中特别严重的问题，因为患有脓毒症的老年患者的发病率和死亡率比年轻患者高得多。事实上，脓毒症是美国重症监护病房老年患者死亡的主要原因。虽然这一问题越来越多地被认识到，但造成这种与年龄相关的脆弱性的根本机制在很大程度上仍然未知。我们研究的长期目标是确定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。在动物模型中也观察到与年龄相关的脓毒症易感性。我们已经表明，老年小鼠遭受显着更高的死亡率比年轻小鼠在两个常用的模型败血症;细菌脂多糖注射诱导的内毒素血症，盲肠结扎和穿刺诱导腹腔内败血症。我们还发现，老年小鼠死亡率的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，老年人体内稳态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易感性。我们的目标是在这个项目中，定义在败血症的小鼠模型的病理生理学和基因表达的年龄相关的改变，并制定策略，以提高老年小鼠的生存与败血症。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基因表达中与年龄相关的改变，以及（3）测试降低脓毒症中与年龄相关的死亡率的可能策略。从这个项目中获得的信息应提供新的治疗策略，以大大降低老年脓毒症患者的死亡率的基础。

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.