Downregulation of Inflamm-aging for Protection Against Organ Damage in Sepsis

老年人占败血症患者的很大比例。器官功能障碍在慢性阻塞性肺疾病患者中常见 严重脓毒症，老年脓毒症患者往往器官损伤更严重，器官持续时间更长 功能障碍。然而，导致陈旧性脓毒症器官损伤/功能障碍加重的机制 患者仍不清楚。这一提议验证了衰老增强和延长的中心假设。 炎症加重器官损伤，阻碍败血症后器官功能的恢复。 中心假说是基于我们在使用动物模型进行的初步研究中的新发现。 败血症。具体地说，我们观察到老年小鼠表现出增强和持续的炎症，以及 更严重的心脏和肾功能障碍，类似于老年脓毒症患者的临床表现。 心肌和肾脏组织中抗衰老蛋白Klotho的衰老相关缺陷 而这种改变的炎症在器官损伤和 功能障碍。此外，脓毒症诱导促炎介质FGF23的过度产生，以及 Klotho具有下调FGF23产生及其促炎活性的新功能。 更重要的是，抗炎细胞因子IL-37上调老年小鼠Klotho表达，并 预防脓毒症的器官功能障碍和死亡率。 我们将追求两个相互关联的具体目标来检验衰老阻碍脑血管疾病恢复的假设 脓毒症后的器官功能通过延长炎症反应和探索治疗方法 促进败血症所致损伤的器官恢复。拟议的研究将涉及到 增龄相关的Klotho缺乏症导致炎症增加和 加重老年脓毒症小鼠的器官损伤/功能障碍，并将阐明其机制 FGF23会加剧炎症。此外，拟议的研究将探索以下治疗潜力： 重组Klotho和IL-37用于保护器官免受损伤/功能障碍。 总体而言，拟议的研究将为了解器官恶化的机制提供见解。 老年脓毒症受试者的损伤/功能障碍并为新药的开发提供临床前信息 下调炎症衰老以保护受影响老年人器官的治疗方法 败血症。

Older adults make a large proportion of sepsis patients. Organ dysfunction is common in patients with severe sepsis, and old septic patients often have more severe organ injury and longer-lasting organ dysfunction. However, the mechanism underlying exacerbated organ injury/dysfunction in old septic patients remain unclear. This proposal tests the central hypothesis that aging enhances and prolongs inflammation to exacerbate organ injury and to impede the recovery of organ function following sepsis. The central hypothesis is based on our novel findings in preliminary studies using an animal model of sepsis. Specifically, we observed that old mice display enhanced and prolonged inflammation, as well as more severe cardiac and renal dysfunction, mimicking the clinical manifestations of old septic patients. Aging-related deficiency in anti-aging protein Klotho in the myocardium and kidney tissue is responsible for the augmented inflammation, and such altered inflammation occupies a major role in organ injury and dysfunction. Further, sepsis induces the over-production of pro-inflammatory mediator FGF23, and Klotho has a novel function in down-regulation of FGF23 production and its pro-inflammatory activity. More importantly, anti-inflammatory cytokine IL-37 up-regulates Klotho expression in old mice and protects against organ dysfunction and mortality in sepsis. We will pursue two interrelated Specific Aims to test the hypothesis that aging impedes the recovery of organ function following sepsis by prolonging inflammation and to explore therapeutic approaches for promotion of organ recovery from injury caused by sepsis. Proposed studies will address the role of aging-related Klotho deficiency in the mechanism underlying the augmented inflammation and exacerbated organ injury/dysfunction in old septic mice and will elucidate the mechanism by which FGF23 augments inflammation. Further, the proposed studies will explore the therapeutic potential of recombinant Klotho and IL-37 for protection of organs against injury/dysfunction. Overall, the proposed studies will provide insights into the mechanisms underlying exacerbated organ injury/dysfunction in old septic subjects and offer preclinical information for development of novel therapeutic approaches for down-regulation inflamm-aging to protect organs in old people affected by sepsis.