Novel Approaches to Maintaining Organ Function in Sepsis

脓毒症每年影响至少170万美国人，导致死亡。 270，000名患者，包括所有医院死亡的30%。不幸的是，没有有效的治疗方法， 脓毒症和脓毒性休克患者。过度的中性粒细胞活化是炎症的关键决定因素 和组织损伤。因此，靶向中性粒细胞活化、迁移和浸润可能是一种治疗方法。 降低脓毒症发病率和死亡率的合理策略。在这个MIRA项目的最后一个资助期间， 我们在中性粒细胞和内皮细胞活化的分子机制方面取得了重大进展， 它们的相互作用，以及脓毒症中肺中的中性粒细胞浸润。我们以前报道过细胞外冷- 诱导型RNA结合蛋白（eCIRP）作为一种新的损伤相关分子模式， 败血症增加炎症并引起急性肺损伤。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，其极化Th 1细胞以产生干扰素β，从而 引发和诱导中性粒细胞产生过量的中性粒细胞胞外陷阱（NET），引起进一步的 组织损伤APAN的连续转移加重了脓毒症并增加了脓毒症动物的死亡率， 提示APAN在脓毒症病理生物学中起关键作用。然而，APAN的定位，诱导， 脓毒症中的效应器功能仍然未知，它们对免疫和认知功能的贡献也是如此。 败血症幸存者的功能障碍。我们最近在计算机上预测并在体外证实，我们的新 发现稳定的RNA模拟物A12以高亲和力结合eCIRP，降低eCIRP对其受体的亲和力， 抑制eCIRP诱导TNF α释放和诱导NETosis的能力。因此，A12是一种新颖而有效的 eCIRP抑制剂，具有减弱eCIRP诱导的APAN在脓毒症中的有害作用的潜力。作为 因此，这项更新MIRA研究计划将解决以下三个关键问题：1）eCIRP如何 诱导APAN，它们的效应子功能是什么？2)APAN如何加重败血症？3)目标定位 eCIRP调节APAN以减轻脓毒症？该研究将为生物医学的发展提供新的方向 通过预防或调节感染性休克的发生来治疗患有脓毒症和脓毒性休克的患者的创新疗法 APAN的新型高度炎症中性粒细胞群。

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.