IL-33 signaling as a target to reduce ventilator-induced lung inflammation

IL-33 信号传导作为减少呼吸机引起的肺部炎症的靶点

• 批准号: 10704302
• 负责人: Guido Musch
• 金额: $ 81.02万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704302
• 关键词: Acute Respiratory Distress Syndrome; Address; Affinity; Allergic inflammation; Binding; Biological; Biological Markers; Biological Response Modifier Therapy; Blocking Antibodies; Cell membrane; Cells; Clinical; Critical Illness; Data; Epidemic; Epithelial; Gene Expression; General Anesthesia; Genetic Transcription; Goals; Hour; Immune; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intensive Care Units; Interleukin-1 Receptors; Interleukin-13; Interleukin-4; Interleukin-5; Interleukin-6; Interruption; Intubation; Knockout Mice; Knowledge; Lead; Light; Link; Lung; MAP Kinase Gene; Measures; Mechanical ventilation; Mechanics; Mediating; Mediator of activation protein; Methods; Modeling; Morbidity - disease rate; Mus; Operating Rooms; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Pilot Projects; Poliomyelitis; Positron-Emission Tomography; Postoperative Period; Process; Production; Proteins; Pulmonary Inflammation; Rattus; Recombinants; Reporter; Reporting; Research; Resolution; Role; Signal Pathway; Signal Transduction; Testing; Th2 Cells; Therapeutic; Therapeutic Intervention; Tidal Volume; Time; Transgenic Organisms; Treatment Efficacy; Ventilator; Ventilator-induced lung injury; clinical practice; clinically relevant; cytokine; effective therapy; experimental study; imaging modality; immunogenicity; improved; in vivo; interest; mechanical pressure; mechanical stimulus; molecular imaging; mortality; mouse model; non-invasive imaging; novel; preventive intervention; public health relevance; receptor; response; stem; therapeutic target; uptake; ventilation

PROJECT SUMMARY/ABSTRACT Since being heralded into clinical practice by the Danish polio epidemic of 1952, positive pressure mechanical ventilation has saved countless lives and enabled the safe practice of surgery under general anesthesia. In recent years, however, it has become clear that mechanical ventilation itself can injure the lung by initiating and propagating an inflammatory process termed ventilator-induced lung injury (VILI). Whereas VILI was initially mainly considered an aggravating factor for critically ill patients with acute respiratory distress syndrome, new evidence suggests that it can occur also in subjects with uninjured lungs undergoing ventilation for other reasons, for example while receiving general anesthesia. The long-term goal of this research is to dissect the mechanisms of VILI and identify strategies to ameliorate it. The proposed studies align with this goal because they investigate a novel role for the IL-33/ST2 signaling pathway by addressing the overarching hypothesis that IL-33 is an upstream pathogenetic effector of VILI through its effect on NF-κB mediated inflammation. This hypothesis will be tested through three closely knit specific aims. Aim 1 will establish the role of IL-33 in VILI by demonstrating that its expression increases with tidal volume, that it parallels the response of established VILI cytokines and NF-κB, and that IL-33 deletion blunts such response. Aim 2 builds on aim 1 by probing the efficacy of IL-33 scavenging with IL-33 decoy receptors as an approach for interrupting IL-33/ST2/NF-κB signaling and decreasing inflammation in VILI. This aim will leverage a novel biologic with high affinity for IL-33 (“IL-33 trap”) that preliminary data suggest could have therapeutic potential. The IL-33 trap will be compared with the more traditional approach of anti-ST2 receptor blocking antibodies. Aim 3 flows from aims 1 and 2 as it will determine for how long the activation of NF-κB triggered by release of mechano- sensitive cytokines like IL-33 persists after ventilation ceases, thus rendering the lung vulnerable to other insults, as are those that can occur in the postoperative period. A distinctive feature that permeates all three aims of this project is the application of a unique molecular imaging method based on positron emission tomography (PET) of NF-κB transcriptional activity to measure the effect of IL-33/ST2 signaling on downstream cytokine expression in vivo, noninvasively, repeatedly and with high spatial resolution. It is expected that the combination of clinically relevant murine ventilation model, novel VILI effector (IL-33, aim 1), therapeutic biologic (IL-33 trap, aim 2), and translational perspective (aim 3), will make the proposed experiments uniquely poised to yield fundamental new knowledge on the pathogenesis of VILI and on potential preventative and therapeutic strategies.

项目总结/摘要 自1952年丹麦脊髓灰质炎流行病进入临床实践以来，正压机械 通气已经挽救了无数的生命，并且使得能够在全身麻醉下安全地进行手术。在 然而，近年来，已经清楚的是，机械通气本身可以通过引发肺损伤， 并传播称为呼吸机诱导的肺损伤（VILI）的炎症过程。而VILI则是 最初主要考虑重症患者急性呼吸窘迫的加重因素 综合征，新的证据表明，它也可以发生在受试者与未受伤的肺进行通气 由于其他原因，例如在接受全身麻醉时。这项研究的长期目标是 剖析VILI的机制，并确定改善它的策略。 目标，因为他们研究了IL-33/ST 2信号通路的新作用， IL-33可能通过影响NF-κB介导而成为VILI的上游致病效应因子 炎症这一假设将通过三个紧密结合的具体目标进行检验。目标1将建立 IL-33在VILI中的作用，通过证明其表达随潮气量增加而增加，其与VLI的发生率平行， IL-33的缺失减弱了已建立的VILI细胞因子和NF-κB的应答，并且IL-33的缺失减弱了这种应答。Aim 2构建 通过探测用IL-33诱饵受体清除IL-33的功效作为中断IL-33的途径， IL-33/ST 2/NF-κB信号转导和减轻VILI中的炎症。这一目标将利用一种新的生物制剂， 对IL-33高亲和力（“IL-33陷阱”）初步数据表明可能具有治疗潜力。的IL-33 trap将与更传统的抗ST 2受体阻断抗体方法进行比较。Aim 3流程 目的1和2，因为它将确定由机械释放触发的NF-κB激活多长时间。 敏感的细胞因子如IL-33在通气停止后仍然存在，从而使肺容易受到其他炎症因子的影响。 如术后可能发生的损伤。一个渗透到这三个领域的显著特征 本项目的目的是应用一种独特的基于正电子发射的分子成像方法 NF-κB转录活性的断层扫描（PET）以测量IL-33/ST 2信号传导对下游细胞的影响。 细胞因子在体内的表达，非侵入性，重复和高空间分辨率。预计该 临床相关鼠通气模型、新型VILI效应子（IL-33，目的1）、治疗性 生物学（IL-33陷阱，目的2）和翻译的角度（目的3），将使所提出的实验独特 准备产生关于VILI的发病机制和潜在的预防和治疗的新知识， 治疗策略