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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：
10616814
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/10616814
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 Cells Epithelium Etiology Exhibits Exposure to Fibroblasts Fibrosis Generations Goals Human Impairment In Vitro Ingestion Injury Knockout Mice Knowledge Ligands Link Lipids Lung Macrophage Macrophage Activation Mediating Medical Modeling Mus Null Lymphocytes Organ Organ failure Oxidative Stress Pathogenesis Pathology Pathway interactions Phenotype Phospholipase A2 Phospholipids Predisposition 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 monocyte mouse model new therapeutic target novel novel therapeutics oxidation phospholipase A2 inhibitor 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，但也可发生在慢性肺损伤中。没有任何已知的病因，如特发性肺纤维化（IPF）。IPF是一种破坏性疾病，从诊断开始的中位生存期约为4年，目前的药物治疗只能适度减缓疾病进展即使是由已知原因引起的纤维化也可能导致艰难的进展过程，因此，更精确地阐明纤维化的发病机制，以鉴定新的治疗靶点。最近对人类纤维化疾病和动物模型的研究已经确定了II型胶原的关键作用，肺泡上皮细胞（AEC 2）损伤和凋亡在间质瘢痕形成的起始中的作用。但将AEC 2损伤/死亡转化为纤维化的下游途径仍不明确。我们的初步数据证明一系列AEC 2损伤驱动其CCL 2/CCL 12的表达，趋化因子参与其中促纤维化单核细胞/巨噬细胞募集。这一反应的重要性得到证实，这表明AEC 2衍生的CCL 12缺陷的小鼠在鼠模型中发展出减弱的纤维化。 AEC 2损伤也可进展为凋亡，伴随其丰富的磷脂氧化储存，我们发现，摄取和积累的氧化磷脂（oxPL）来源于凋亡AEC 2（释放或保留在凋亡小体内）诱导促纤维化表型转换巨噬细胞中。将凋亡AEC 2或oxPL施用到未损伤小鼠的肺中足以驱动肺纤维化，并且这种摄取由CD 36介导。oxPL的积累，巨噬细胞的活性也是由它的催化剂决定的，我们已经证明，它主要受溶酶体的调节。磷脂酶A2（LPLA 2）。我们的初步结果表明，oxPL的快速细胞内降解，肺泡巨噬细胞中的LPLA 2可使巨噬细胞活化最小化。与常驻巨噬细胞相比，单核细胞衍生的巨噬细胞被募集到损伤的肺中， oxPL的积累是由于它们降低LPLA 2的表达。这些初步数据激发了我们的中心假设，即AEC 2损伤/凋亡导致协调的细胞凋亡。从受损的AECs中产生的CCL 12吸引单核细胞衍生的巨噬细胞到AECs的反应。肺泡空间，在那里它们吞噬并积累oxPL，导致强烈的促纤维化活化。我们将采用体内原代小鼠和人类巨噬细胞的体外研究，寻求多方面的方法小鼠实验使用新的转基因小鼠、骨髓移植嵌合体和互补的肺纤维化模型。我们已经形成了一个协同团队，在脂质，单核细胞/巨噬细胞， AEC2我们的研究项目专门解决了纤维化发病机制中公认的知识缺口。重要的是，这些研究的结果将定义以前未探索的机制，并将为新疗法的开发提供信息。