Oxidized Phospholipids Derived from Apoptotic Pneumocytes Drives Macrophage Activation and Initiates Lung Fibrosis

凋亡肺细胞衍生的氧化磷脂驱动巨噬细胞激活并引发肺纤维化

基本信息

批准号：
10470837
负责人：
KEVIN KEEWOUN KIM
金额：
$ 61.7万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10470837
关键词：
Address Alveolar Alveolar Macrophages Alveolar fibrosis Animal Model Apoptosis Apoptotic Attenuated Automobile Driving Bleomycin Bone Marrow Bone Marrow Transplantation CCL2 gene CD36 gene Catabolism Cells Cessation of life Chimera organism Chronic Cicatrix Data Defect Development Diagnosis Disease Disease Progression Disease model Enzymes Epithelial Epithelial Cells Etiology Exhibits Exposure to Fibroblasts Fibrosis Generations Goals Human Impairment In Vitro Ingestion Injury Knockout Mice Knowledge Lead Ligands Link Lipids Lung Macrophage Activation Mediating Medical Modeling Mus Null Lymphocytes Organ Organ failure Oxidative Stress Oxides Pathogenesis Pathology Pathway interactions Phenotype Phospholipase A2 Phospholipids Profibrotic signal Publishing Pulmonary Fibrosis Recombinant Proteins Recombinants Reporting Research Project Grants Role Sampling Secondary to Shortness of Breath Signal Pathway Signal Transduction Systemic disease Testing Time Transforming Growth Factor beta Transgenic Mice Translating Transplantation Chimera alveolar epithelium cell injury chemokine experimental study fibrotic lung fibrotic lung disease idiopathic pulmonary fibrosis in vivo inhibitor injured interstitial lung injury macrophage monocyte mouse model new therapeutic target novel novel therapeutics oxidation pneumocyte receptor recruit repaired response surfactant targeted treatment tissue injury uptake

项目摘要

Project Summary Progressive lung fibrosis is a feature of systemic diseases and chronic injury but can also occur in the absence of any known etiology as with Idiopathic Pulmonary Fibrosis (IPF). IPF is a devastating disorder with a median survival of ~4 years from time of diagnosis and current medical therapy only modestly slows disease progression. Even fibrosis from known causes can lead to a difficult progressive course, thsu it is vital that the pathogenesis of fibrosis is more precisely elucidated in order to identify novel therapeutic targets. Recent studies from both human fibrotic diseases and animal models have identified a critical role for type II alveolar epithelial cell (AEC2) injury and apoptosis in the initiation of interstitial scarring. However, the downstream pathways that translate AEC2 injury/death into fibrosis remain undefined. Our preliminary data demonstrate that an array of AEC2 insults drives their expression of CCL2/CCL12, chemokines involved in pro-fibrotic monocyte/macrophage recruitment. The importance of this response was confirmed by demonstrating that mice deficient in AEC2-derived CCL12 developed attenuated fibrosis in a murine model. AEC2 injury can also progress to apoptosis with an accompanying oxidation of their abundant phospholipid stores, and we discovered that uptake and accumulation of oxidized phospholipid (oxPL) derived from apoptotic AEC2s (either released or retained within apoptotic bodies) induces a pro-fibrotic phenotypic switch in the ingesting lung macrophage. Administration of apoptotic AEC2s or oxPL into the lungs of uninjured mice is sufficient to drive lung fibrosis and this uptake is mediated by CD36. The accumulation of oxPL within macrophages is also determined by its catabolism which we have shown is regulated primarily by lysosomal phospholipase A2 (LPLA2). Our preliminary results indicate that the rapid intracellular degradation of oxPL by LPLA2 in alveolar macrophages can minimize macrophage activation. Compared to resident macrophages, monocyte-derived macrophages that are recruited to the injured lung exhibit a greater pro-fibrotic response to oxPL accumulation due to their decreases expression of LPLA2. These preliminary data motivate our central hypothesis that AEC2 injury/apoptosis results in a coordinated response in which the elaboration of CCL12 from injured AECs attracts monocyte-derived macrophages to the alveolar space where they engulf and accumulate oxPL resulting in robust pro-fibrotic activation. We will pursue a multifaceted approach using in vitro studies of primary murine and human macrophages with in vivo mouse experiments using novel transgenic mice, bone marrow transplant chimeras, and complementary models of lung fibrosis. We have formed a synergistic team with expertise in lipids, monocyte/macrophages, and AEC2s. Our research project specifically addresses a recognized knowledge gap in fibrosis pathogenesis. Importantly, the results of these studies will define previously unexplored mechanisms that critically regulate fibrosis and will inform the development of novel therapies.

项目摘要进行性肺纤维化是全身性疾病和慢性损伤的特征，但也可能发生没有任何已知病因，即特发性肺纤维化（IPF）。 IPF是一种毁灭性疾病，有自诊断和当前医疗疗法从诊断和当前的医疗疗法开始的中位生存期仅减慢疾病进展。即使是来自已知原因的纤维化也可能导致艰难的进步过程，这一点至关重要为了鉴定新的治疗靶标，纤维化的发病机理更精确地阐明。来自人类纤维化疾病和动物模型的最新研究已经确定了II型的关键作用肺泡上皮细胞（AEC2）损伤和凋亡的开始。但是，将AEC2损伤/死亡转化为纤维化的下游途径仍然不确定。我们的初步数据证明AEC2的一系列侮辱驱动其表达CCL2/CCL12，趋化因子涉及促纤维细胞/巨噬细胞募集。该回应的重要性已得到证实证明缺乏AEC2衍生的CCL12的小鼠在鼠模型中会导致纤维化减弱。 AEC2损伤也可以通过伴随其丰富磷脂的氧化而发展为凋亡商店，我们发现源自氧化磷脂（OXPL）的吸收和积累凋亡AEC2S（释放或保留在凋亡体内）会诱导促纤维化表型开关在摄入的肺巨噬细胞中。将凋亡AEC2S或OXPL施用到未受伤的小鼠的肺中足以驱动肺纤维化，这种摄取是由CD36介导的。 OXPL在巨噬细胞还取决于其分解代谢，我们表明的主要由溶酶体调节磷脂酶A2（LPLA2）。我们的初步结果表明，OXPL的细胞内降解快速肺泡巨噬细胞中的LPLA2可以最大程度地减少巨噬细胞的激活。与常驻巨噬细胞相比募集到受伤的肺部的单核细胞衍生的巨噬细胞表现出更大的促纤维化反应 OXPL由于其降低LPLA2的表达而产生的。这些初步数据激发了我们的中心假设，即AEC2损伤/凋亡导致协调在受伤的AEC中阐述CCL12的反应吸引了单核细胞衍生的巨噬细胞它们吞噬并积累OXPL的肺泡空间，导致稳健的促纤维激活。我们将使用体内原代鼠和人类巨噬细胞的体外研究采用多方面的方法使用新型转基因小鼠，骨髓移植嵌合体和互补的小鼠实验肺纤维化模型。我们组成了一个协同的团队，具有脂质，单核细胞/巨噬细胞的专业知识，和AEC2S。我们的研究项目专门解决了纤维化发病机理中公认的知识差距。重要的是，这些研究的结果将定义以前未开发的机制，这些机制严格调节纤维化并将告知新型疗法的发展。