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Modifiable Determinants of Mortality in Neonatal Sepsis

新生儿败血症死亡率的可改变决定因素

基本信息

批准号：
10409728
负责人：
James Lawrence Wynn
金额：
$ 38.13万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409728
关键词：
37 weeks gestation Acute Acute Lung Injury Address Adult Age Attenuated Bacteremia Birth Blood Cells Cessation of life Child Chronic Clinical Communication Complement Development Diagnosis Environment Exhibits Exposure to Foundations Fungemia Histologic Human Immune response Incidence Infant Infection Inflammasome Inflammatory Injury Interleukin-1 Interleukin-1 beta Interleukin-17 Interleukin-18 Interleukins Intervention Investigation Knowledge Life Ligands Lung Mediator of activation protein Messenger RNA Modeling Morbidity - disease rate Mortality Determinants Mus Necrosis Neonatal Neurodevelopmental Impairment Newborn Infant Outcome Pathologic Pathway interactions Pharmacology Plasma Population Positioning Attribute Pregnancy Premature Infant Process Production Proteins Proteomics Publishing Research Personnel Risk Role Savings Secondary to Sepsis Signal Pathway Signal Transduction Survivors Testing Therapeutic Intervention Therapeutic Trials Tissues Transcript antimicrobial body system cost cytokine immunological status in utero interleukin-18 binding protein interleukin-23 mortality neonatal mice neonatal sepsis neonate novel organ injury paracrine premature preterm newborn prevent receptor sepsis induced acute lung injury septic systemic inflammatory response therapeutic target tissue injury transcriptomics γδ T cells

项目摘要

PROJECT SUMMARY Neonatal sepsis is one of the most difficult and costly problems to treat and prevent. Despite antimicrobial therapy, 39% of neonates with sepsis die or suffer major chronic morbidity. Although sepsis mortality and morbidity is bimodal, with peaks at the extremes of age (very old and very young), investigations of the neonatal-host immune response to sepsis and the mechanisms behind poor long-term outcomes have lagged behind older children and adults. Preterm neonates differ from more mature populations in terms of their baseline immune status. For example, healthy, uninfected human neonates have elevated levels of circulating IL-18 when compared to adults and exhibit increased IL-18 production with infection. Recently, we showed that IL-18 deletion protected neonates from sepsis mortality and conversely, exposure to IL-18 to mimic the human preterm condition resulted in gut injury, enhanced systemic inflammation, increased bacteremia and mortality in murine neonates with sepsis. Following IL-18 exposure in septic mice, IL-17A transcript was elevated early and exclusively in the gut and lung, and plasma IL-17A protein was 140-fold greater than levels in septic mice without IL-18 exposure. We described a novel deleterious inflammatory signaling pathway in the preterm infant led by IL-18, dependent upon IL-1R1 signaling, and culminating in excessive IL-17A production by γδT cells that was mechanistically responsible for mortality. We also demonstrated that we could reverse IL-18- enhanced sepsis mortality via pharmacologic IL-17 receptor (IL-17R) blockade. We now show this treatment is associated with a reduction in acute lung injury (ALI), the penultimate pathway to death in human neonates. The studies proposed in this application are prerequisite to therapeutic trials and will test the hypotheses that IL-1α is the primary ligand that leads to mortality and deleterious IL-17A production in the gut while IL-1β is the primary ligand for IL-17A production in the lung (Aim 1), that IL-1R1-dependent IL-17A production by γδT cells in both the gut and the lung is augmented by IL-23 (Aim 2), and ALI is a principal and preventable mechanism for death in neonates with sepsis and is secondary to primary gut injury (Aim 3). First, we will determine the IL- 1R1 ligand(s) responsible for mortality and the production of IL-17A in the gut and lung during neonatal sepsis (Aim 1). Second, we will identify whether there is an additional absolute requirement of IL-23 for IL-17A production by γδT cells downstream from IL-1R1 signaling in the gut and in the lung (Aim 2). Finally, we will resolve whether IL-17A is an ideal therapeutic target to protect neonatal mice from sepsis-induced acute lung injury (Aim 3). Cumulatively, we will search for hitherto unknown contributors and regulators of this unique pathway and thus generate new knowledge about the poorly understood parameters of neonatal sepsis through determination of the role of IL-18/IL-1/IL-17A signaling in sepsis-induced organ injury.

项目摘要新生儿败血症是治疗和预防最困难和最昂贵的问题之一。尽管抗菌治疗期间，39%的新生儿败血症死亡或患有严重的慢性病。虽然败血症死亡率和发病率是双峰型的，在年龄的极端（非常老和非常年轻）达到高峰，脓毒症的宿主免疫反应和长期不良结局背后的机制已经落后落后于年龄较大的儿童和成人。早产儿与更成熟的人群在其基线免疫状态。例如，健康的、未感染的人类新生儿具有升高的循环血凝素水平。 IL-18，并且随着感染表现出IL-18产生增加。最近，我们发现， IL-18缺失可保护新生儿免于败血症死亡，相反，暴露于IL-18以模拟人早产导致肠道损伤、全身炎症增强、菌血症和死亡率增加在患有败血症的小鼠新生儿中。在脓毒症小鼠中IL-18暴露后，IL-17 A转录早期升高，并且仅在肠和肺中，血浆IL-17 A蛋白比脓毒症小鼠的水平高140倍没有IL-18暴露。我们描述了一种新的有害炎症信号通路在早产儿婴儿由IL-18导致，依赖于IL-1 R1信号传导，并最终通过γδT产生过量IL-17 A 这些细胞在机械上导致死亡。我们还证明了我们可以逆转IL-18，通过药理学IL-17受体（IL-17 R）阻断提高脓毒症死亡率。我们现在证明这种治疗是与急性肺损伤（ALI）的减少相关，急性肺损伤是人类新生儿死亡的倒数第二个途径。本申请中提出的研究是治疗试验的先决条件，并将测试以下假设： IL-1α是导致肠道中死亡和有害IL-17 A产生的主要配体，而IL-1β是导致肠道中死亡和有害IL-17 A产生的主要配体。肺中IL-17 A产生的主要配体（目的1），即γδT细胞产生IL-1 R1依赖性IL-17 A IL-23可增强肠和肺的炎症反应（目的2），而ALI是一种主要的可预防机制导致新生儿败血症死亡，并继发于原发性肠道损伤（目的3）。首先，我们将确定IL- 1 R1配体与新生儿败血症期间肠道和肺中的死亡率和IL-17 A产生有关 (Aim 1）。其次，我们将确定是否存在IL-17 A对IL-23的额外绝对需求肠和肺中IL-1 R1信号传导下游的γδT细胞产生的免疫应答（Aim 2）。最后我们将解决IL-17 A是否是保护新生小鼠免受脓毒症诱导的急性肺损伤的理想治疗靶点伤害（目标3）。累积起来，我们将寻找迄今未知的贡献者和监管机构，这一独特的途径，从而产生关于新生儿败血症的知之甚少的参数的新知识通过确定IL-18/IL-1/IL-17 A信号传导在脓毒症诱导的器官损伤中的作用。