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.

项目摘要/摘要 自1952年丹麦脊髓灰质炎疫情宣布进入临床以来，正压机械 通风拯救了无数人的生命，并使全身麻醉下的手术得以安全进行。在……里面 然而，最近几年，已经很清楚，机械通气本身可以通过启动 以及传播一种称为呼吸机诱导的肺损伤(VILI)的炎症过程。而Vili则是 最初主要被认为是危重患者急性呼吸窘迫的加重因素 综合症，新的证据表明，它也可以发生在接受机械通气的肺未受损的受试者中。 出于其他原因，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，确定改善VILI的策略。拟议的研究符合这一点 目的是因为他们研究了IL-33/ST2信号通路的一个新角色，通过解决主要的 IL-33通过影响NF-κB而成为VILI上游致病效应因子的假说 发炎。这一假设将通过三个紧密相连的具体目标来检验。目标1将建立 IL-33在VILI中的作用通过证明其表达随着潮气量的增加而增加，它与 已建立的VILI细胞因子和NF-κB的反应，而IL-33的缺失减弱了这种反应。AIM 2构建 探讨IL-33诱骗受体清除IL-33作为阻断途径的作用 IL-33/ST2/NF-κB信号转导与VILI抗炎作用这个目标将利用一种新的生物学和 对IL-33的高亲和力(“IL-33陷阱”)，初步数据表明可能具有治疗潜力。IL-33 TRAP将与更传统的抗ST2受体封闭抗体方法进行比较。AIM 3流程 从目标1和目标2，因为它将决定由释放机械-κ-B触发的核转录因子-DNA B的激活多长时间。 在停止换气后，像IL-33这样的敏感细胞因子仍然存在，从而使肺容易受到其他 侮辱，就像那些可能在术后期间发生的那样。一个贯穿于这三个领域的独特特征 该项目的目标是应用一种独特的基于正电子发射的分子成像方法。 核因子-κB转录活性断层扫描检测IL-33/ST2信号对下游的影响 细胞因子在体内表达，无创，重复，空间分辨率高。预计将会有 临床相关的小鼠呼吸机模型、新型VILI效应器(IL-33，Aim 1)、治疗性的组合 生物学(IL-33 TRAP，目标2)和翻译视角(目标3)将使拟议的实验独树一帜 准备对VILI的发病机制和潜在的预防和治疗产生基本的新知识 治疗策略。