Sequential release of IL-1alpha and IL-1beta leads to a two-hit model of acute lung injury

IL-1α和IL-1β的顺序释放导致急性肺损伤的二次打击模型

基本信息

批准号：
9195126
负责人：
Kenichi Shimada
金额：
$ 43.75万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195126
关键词：
Acute Acute Lung Injury Address Adult Respiratory Distress Syndrome Alveolar Animal Model Area Autophagocytosis Binding Biogenesis Biological Preservation Blood Blood Vessels Breathing CASP1 gene Cell Death Cellular Stress Cessation of life Cleaved cell Clinical Critical Illness Cytokine Signaling DNA Binding Data Development Edema Endothelial Cells Extravasation Hypoxemia Infiltration Inflammasome Inflammation Inflammatory Injury Interleukin-1 Interleukin-1 Receptors Interleukin-1 alpha Interleukin-1 beta Interleukins Lead Lipopolysaccharides Lung Lung Inflammation Mechanical ventilation Mediating Mitochondria Mitochondrial DNA Modeling Mus Necrosis Neutrophil Infiltration Oxides Pathogenesis Pathology Patients Production Recruitment Activity Reporting Resolution Risk Role Sepsis Signal Transduction Silicon Dioxide Smooth Muscle Myocytes Stromal Cells Syndrome System Testing Therapeutic Time Tissues Work base chemokine cytokine improved interest lung injury macrophage mitochondrial dysfunction mortality mouse model neutralizing antibody new therapeutic target novel prevent public health relevance repaired synergism

项目摘要

DESCRIPTION (provided by applicant): Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome of acute lung injury (ALI) characterized by a sudden onset and a profound inability of the lungs to oxygenate the blood (hypoxemia). There are no known therapies for ARDS except using low volumes on mechanical ventilation (MV), which still has an unacceptably high mortality rate of 30%. The combination of sepsis plus MV (`two-hit") significantly increases the risk for developing ARDS. Interleukin-1α (IL-1α) and IL-1β are implicated in the pathogenesis of ARDS. While both IL-1α and IL-1β are produced in a pro form, cleavage of IL-1β is required for its secretion and activation, while both the cleaved and pro-form of IL-1α are active. Our preliminary data indicate that pro- IL-1α is released from necrotic MΦ after LPS inhalation, which leads to vascular leakage and PMN recruitment into the lungs. However, for maturation and release of IL-1β, activation of the inflammasome is required. We showed that NLRP3 inflammasome is activated in MΦ by mitochondrial (Mt) dysfunction followed by oxidized MtDNA binding to NLRP3. Mt damage simultaneously leads to activation of repair systems such as autophagy and mitophagy that oppose cell death. Recent reports suggest that both mitophagy and Mt biogenesis may serve a protective role in sepsis and mitigate ALI. We developed a mouse model in which MV triggers MΦ Mt dysfunction and cell death, and intratracheal LPS followed by MV lead to sequential release of IL-1α and IL-1β secretion and the development of ALI, with PMN infiltration, alveolar edema, chemokine secretion, and hypoxemia. When IL-1 signaling was disrupted by the absence of caspase-1 or NLRP3, or by IL-1R antagonist, mice demonstrated equal levels of inflammation compared to controls, but failed to develop hypoxemia, indicating that the mechanism of hypoxemia in ALI is dependent on IL-1 signaling. Both endothelial cells (EC) and smooth muscle cells (SMC) have been implicated in the mechanism of ALI-induced hypoxemia and are targets of IL-1 signaling. These observations lead us to hypothesize that the development of ALI and hypoxemia in LPS+MV requires sequential release of IL-1α from LPS-induced necrotic MΦ, followed by IL-1 secretion by NLRP3 inflammasome activation in AM during MV. Mitophagy and mitochondrial biogenesis oppose LPS+MV induced acute lung injury and hypoxemia by inhibiting inflammasome activation and preserving tissue function. To test these hypotheses we propose the following specific aims: 1) Determine the role of IL-1α in the development of hypoxemia in LPS+MV acute lung injury. 2) Determine the role of IL-1 signaling in LPS+MV-induced hypoxemia. 3) Determine the role of mitophagy and mitochondria biogenesis in LPS+MV acute lung injury. These studies will help determine novel mechanisms underlying IL-1α and dependent hypoxemia in ALI and ARDS, and will identify a new area of potential therapeutics for sepsis patients with ARDS on MV, a condition that still carries over 30% mortality rate for which no treatments currently exist.

描述（由申请人提供）：急性呼吸窘迫综合征（ARDS）是一种急性肺损伤（ALI）的临床综合征，其特征是突然发作且肺部严重无法给血液供氧（低氧血症）。目前尚无已知的治疗方法。对于 ARDS，除了使用低容量机械通气 (MV) 外，其死亡率仍然高达 30%，令人无法接受。脓毒症加 MV（“两次打击”）的组合显着增加。 IL-1α (IL-1α) 和 IL-1β 与 ARDS 的发病机制有关，虽然 IL-1α 和 IL-1β 均以原形式产生，但其裂解需要 IL-1β。分泌和激活，而 IL-1α 的裂解形式和前体形式均具有活性。我们的初步数据表明，IL-1α 前体从坏死中释放。吸入 LPS 后的 MΦ，导致血管渗漏和 PMN 募集到肺部。然而，为了成熟和释放 IL-1β，需要激活炎症小体。我们发现，线粒体 (Mt) 功能障碍会激活 MΦ 中的 NLRP3 炎症小体。随后氧化的 MtDNA 与 NLRP3 结合，同时导致修复系统的激活，例如抵抗细胞死亡的自噬和线粒体自噬。表明线粒体自噬和 Mt 生物发生可能在脓毒症中发挥保护作用并减轻 ALI。我们开发了一种小鼠模型，其中 MV 触发 MΦ Mt 功能障碍和细胞死亡，气管内 LPS 和 MV 导致 IL-1α 和 IL 的顺序释放。当 IL-1 信号传导被破坏时，-1β 分泌和 ALI 的发展，伴有 PMN 浸润、肺泡水肿、趋化因子分泌和低氧血症。在缺乏 caspase-1 或 NLRP3 或通过 IL-1R 拮抗剂的情况下，小鼠与对照组相比表现出相同水平的炎症，但未出现低氧血症，表明 ALI 中低氧血症的机制依赖于 IL-1 两种内皮信号传导。细胞 (EC) 和平滑肌细胞 (SMC) 与 ALI 诱导的低氧血症机制有关，并且是 IL-1 信号传导的靶标。这些观察结果使我们追查 ALI 和低氧血症的发展。 LPS+MV 需要从 LPS 诱导的坏死 MΦ 中顺序释放 IL-1α，随后 MV 期间 AM 中 NLRP3 炎性体激活分泌 IL-1，线粒体自噬和线粒体生物合成通过抑制来对抗 LPS+MV 诱导的急性肺损伤和低氧血症。为了检验这些假设，我们提出以下具体目标：1) 确定 IL-1α 在低氧血症发生中的作用。 2) 确定 IL-1 信号在 LPS+MV 诱导的低氧血症中的作用 3) 确定线粒体自噬和线粒体生物发生在 LPS+MV 急性肺损伤中的作用这些研究将有助于确定新的。 ALI 和 ARDS 中 IL-1α 和 p 依赖性低氧血症的潜在机制，并将确定针对 MV 脓毒症 ARDS 患者的潜在治疗新领域，这种情况仍然存在目前尚无治疗方法，死亡率高达 30%。