IL-1beta in the Development of Hypoxemia in Acute Lung Injury

IL-1β 在急性肺损伤低氧血症发展中的作用

基本信息

批准号：
9185339
负责人：
Heather Jones
金额：
$ 17.11万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9185339
关键词：
Acute Acute Lung Injury Adult Respiratory Distress Syndrome Affect Alveolar Alveolar Macrophages Animal Model Applications Grants Area Blood Blood capillaries Breathing CASP1 gene Cell Death Cellular Stress Cessation of life Cleaved cell Clinical Clinical Trials Complex Critical Illness Data Development Disease Edema Extravasation Failure Future Gases Hypoxemia Hypoxia Inflammasome Inflammation Inflammatory Injury Interleukin-1 beta Lead Leucine-Rich Repeat Lipopolysaccharides Literature Lung Lung Inflammation Lung diseases Mechanical ventilation Mediating Mentors Modeling Mus Neutrophil Infiltration Nitric Oxide Nitric Oxide Synthase Oxygen Pathogenesis Pathway interactions Patients Physiology Pneumonia Production Proteins Research Risk Role Sepsis Shock Signal Transduction Syndrome Testing Tidal Volume Toll-like receptors Translating United States Vasodilation anakinra base capillary chemokine cytokine innovation interest lung injury macrophage marenostrin mitochondrial dysfunction mortality mouse model novel prevent public health relevance receptor synergism vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome of acute lung injury characterized by a sudden onset and a profound inability of the lungs to oxygenate the blood (hypoxemia). ARDS has a mortality rate of 30% and is responsible for 75,000 deaths annually in the United States despite extensive research efforts. The combination of sepsis plus mechanical ventilation significantly increases the risk for developing ARDS. Therefore, a two-hit model of acute lung injury is of great interest and has been studied extensively in animal models. However, the specific mechanisms underlying the development of acute lung injury through synergy of sepsis and mechanical ventilation (MV) remain unknown. Interleukin 1β (IL-1β) is implicated in the pathogenesis of ARDS, and its secretion is regulated by an intracellular complex termed the NLRP3 inflammasome, which we recently demonstrated is activated in macrophages by mitochondrial dysfunction and is associated with cell death. We developed a mouse model in which MV triggers macrophage mitochondrial dysfunction and cell death, and inhaled lipopolysaccharide (LPS) and MV together lead to IL-1β secretion and the development of acute lung injury, as demonstrated by neutrophil infiltration, alveolar edema, chemokine secretion, and hypoxemia. Interestingly, when IL-1β signaling was disrupted by the absence of caspase-1 or NLRP3, or by the administration of IL-1R antagonist Anakinra, we observed significant improvement in the development of hypoxemia without significant effects on neutrophil infiltration or alveolar leakage, indicating that the mechanism causing hypoxemia in lung injury is independent of lung inflammation but dependent on IL- 1β signaling. These data suggest a novel role for IL-1β and the NLRP3 inflammasome, specifically in the hypoxemia associated with acute lung injury and ARDS. We hypothesize that hypoxic pulmonary vasoconstriction, in which blood is diverted away from areas of poor gas exchange, can help to explain how the development of hypoxemia can be mechanistically distinct from inflammation. Literature suggests that IL- 1β may modulate hypoxic pulmonary vasoconstriction by affecting nitric oxide production in the lung. Indeed, we found that MV increases expression of nitric oxide synthase 2 (NOS2) and nitric oxide production in the lung, and that Nos2-deficient mice were protected from the development of acute lung injury-related hypoxemia. Based on these data, the central hypothesis for this mentored K08 grant application is that the development of hypoxemia in acute lung injury requires NLRP3 inflammasome activation and IL-1β secretion, and that the mechanism of hypoxemia is primarily through IL-1β effects on hypoxic pulmonary vasoconstriction. We now propose to test our hypothesis through the following aims: Aim 1 is to determine the role of alveolar macrophages in the development of hypoxemia in acute lung injury; Aim 2 is to determine the role of nitric oxide in IL-1β-dependent hypoxemia in acute lung injury; and Aim 3 is to determine if NLRP3 and IL-1β signaling in acute lung injury disrupts hypoxic pulmonary vasoconstriction.

描述（由适用提供）：急性呼吸窘迫综合征（ARDS）是急性肺损伤的临床综合征，其特征是突然发作和肺部无法氧合血液（低氧血症）。 ARDS的死亡率为30％，在美国目的地广泛的研究工作中每年造成75,000人死亡。败血症和机械通气的组合显着增加了发展ARD的风险。因此，急性肺损伤的两次打击模型引起了人们的极大兴趣，并且在动物模型中进行了广泛的研究。然而，通过败血症和机械通气（MV）的协同作用，急性肺损伤发展的具体机制尚不清楚。白介素1β（IL-1β）在ARDS的发病机理中实现，其分泌受到称为NLRP3炎症体的细胞内复合物的调节，我们最近证明的是通过线粒体功能障碍在巨噬细胞中激活的，并与细胞死亡有关。我们开发了一种小鼠模型，其中MV会触发巨噬细胞线粒体功能障碍和细胞死亡，并遗传脂多糖（LPS）和MV一起导致IL-1β分泌以及急性肺损伤的发展，如中性粒细胞浸润，阳性降解性，阳性肿瘤，脂质性湿气，趋化因子性，趋化因子性，趋氧化物和过度氧基化。 IL-1β信号传导因缺乏caspase-1或nlrp3或给予IL-1R拮抗剂Anakinra而破坏了IL-1β信号传导，我们观察到在缺氧的发展中没有显着改善，而没有对中性粒细胞浸润或肺泡泄漏显着影响，表明引起低氧损伤的机制，导致肺损伤对Lung Intent in Indent Intent in ventention Intention Intent Intent Intent Intent Intent Incection Il Il iNECTINDICTINDICTIDER IND ILICERTIDER ILIL ILIL。这些数据表明，IL-1β和NLRP3炎症体的新作用，特别是与急性肺损伤和ARDS相关的低氧血症。我们假设缺氧性血管收缩，其中血液从不良的气体交换区域转移出来，可以帮助解释低氧血症的发展如何在机械上与感染不同。文献表明，IL-1β可以通过影响肺中一氧化氮的产生来调节低氧肺血管收缩。实际上，我们发现MV增加了肺中一氧化氮合酶2（NOS2）和一氧化氮的产生的表达，并保护了NOS2缺陷小鼠免受与急性肺损伤相关低氧血症的发展。基于这些数据，该问题的K08授予应用的中心假设是，急性肺损伤中低氧血症的发展需要NLRP3炎性体激活和IL-1β分泌，而低氧良性的机制是通过IL-1β对低氧性肺部血管促进的影响。现在，我们建议通过以下目的检验我们的假设：目标1是确定肺泡巨噬细胞在低氧血症发展中急性肺损伤中的作用；目的2是确定一氧化氮在IL-1β依赖性低氧血症中的作用；目标3是确定急性肺损伤中的NLRP3和IL-1β信号传导是否会破坏低氧肺血管收缩。