Novel Approaches to Maintaining Organ Function in Sepsis

项目描述：败血症每年影响至少170万美国人，导致 27万名患者，占所有医院死亡人数的30%。不幸的是，目前还没有有效的治疗方法 败血症和感染性休克患者。中性粒细胞过度激活是炎症的关键决定因素 脓毒症时的组织损伤。因此，靶向中性粒细胞的激活、迁移和渗透可能是一种 减少脓毒症发病率和死亡率的合理策略。在米拉项目的最后一个资助期内， 我们在中性粒细胞和内皮细胞激活的分子机制方面取得了重大进展， 在脓毒症时，它们的相互作用和中性粒细胞在肺内的渗透。我们之前曾报道过细胞外冷- 诱导型RNA结合蛋白(ECIRP)作为一种新的损伤相关分子模式分子 败血症会增加炎症，造成急性肺损伤。为了继续我们的Mira计划，我们的目标是 探索eCIRP诱导的中性粒细胞表型和功能特征的深刻见解 可能会加重脓毒症时的器官损伤。我们发现了一个以前未知的中性粒细胞群体 抗原提呈、T细胞活化和衰老表型，我们称之为抗原提呈衰老 中性粒细胞(APAN)。APAN产生IL-12，使Th1细胞极化，产生干扰素-，从而 启动和诱导中性粒细胞产生过量的中性粒细胞胞外陷阱(Net)，导致进一步 组织损伤。过继转移APAN加重了败血症，增加了败血症动物的死亡率， 这表明Apans在脓毒症的病理生物学中起着关键作用。然而，Apans的本地化，诱导， 败血症中的效应器功能以及它们对免疫和认知的贡献仍不清楚。 败血症幸存者的功能障碍。我们最近在电子计算机上预测，并在体外证实我们的新的 发现稳定的模拟A12的RNA与eCIRP高亲和力结合，降低eCIRPs对其受体的亲和力， 抑制eCIRP诱导肿瘤坏死因子释放和诱导网织红细胞聚集的能力。因此，A12是一种新颖而有效的 ECIRP抑制剂，有可能减轻eCIRP在脓毒症中诱导的APAN的有害影响。AS 因此，此次更新的MIRA研究计划将解决以下三个关键问题：1)eCIRP如何 诱导Apans，它们的效应器功能是什么？2)Apans如何加重败血症？3)靶向 ECIRP调节APAN以缓解脓毒症？提出的研究将为今后的发展指明新的方向。 治疗败血症和感染性休克患者的创新疗法通过预防或调节 猩猩新的高炎症性中性粒细胞群。

PROJECT DESCRIPTION: Sepsis affects at least 1.7 million Americans annually, causing the death of 270,000 patients and including 30% of all hospital deaths. Unfortunately, there are no effective therapies for patients with sepsis and septic shock. Excessive neutrophil activation is a critical determinant of inflammation and tissue injury in sepsis. Therefore, targeting neutrophil activation, migration, and infiltration may be a rational strategy to reduce sepsis morbidity and mortality. During the last funding period of this MIRA project, we have made significant advances in the molecular mechanism of neutrophil and endothelial cell activation, their interaction, and neutrophil infiltration in the lungs in sepsis. We previously reported extracellular cold- inducible RNA-binding protein (eCIRP) as a new damage-associated molecular pattern molecule released in sepsis to increase inflammation and cause acute lung injury. To continue our MIRA program, we aim to explore the deep insights into neutrophils’ phenotypic and functional characteristics induced by eCIRP that may aggravate organ injury in sepsis. We have discovered a previously unknown neutrophil population with antigen-presenting, T-cell activating, and aged phenotypes, which we named antigen-presenting aged neutrophils (APANs). APANs produce IL-12, which polarizes Th1 cells to generate interferon-, thereby priming and inducing neutrophils to produce excessive neutrophil extracellular traps (NETs), causing further tissue injury. Adoptive transfer of APANs aggravated sepsis and increased the mortality of septic animals, suggesting that APANs play a critical role in sepsis pathobiology. However, APANs’ localization, induction, and effector functions in sepsis remain unknown, as does their contribution to the immune and cognitive dysfunction of sepsis survivors. We have recently predicted in silico and confirmed in vitro that our newly discovered stable RNA mimic A12 binds to eCIRP with high affinity, decreasing eCIRPs affinity for its receptor, inhibiting eCIRP’s ability to induce TNF release and to induce NETosis. Thus, A12 is a novel and potent eCIRP inhibitor with the potential to attenuate the detrimental effects of eCIRP-induced APANs in sepsis. As such, this renewal MIRA research program will address the following three key questions: 1) How does eCIRP induce APANs, and what are their effector functions? 2) How do APANs aggravate sepsis? 3) Does targeting eCIRP regulate APANs to mitigate sepsis? The proposed research will lead to a new direction for developing innovative therapeutics to treat patients suffering from sepsis and septic shock by preventing or modulating the novel hyperinflammatory neutrophil population of APANs.