LOX-1 as a protective countermeasure in response to lung infection

LOX-1 作为应对肺部感染的保护性对策

基本信息

批准号：
10690260
负责人：
Lee Quinton
金额：
$ 70.35万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2023-06-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10690260
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Address Alveolar Alveolar Macrophages Alveolitis Anti-Inflammatory Agents Atherosclerosis Biological Biological Process Biology Blood Circulation Cardiovascular Diseases Cells Cessation of life Clinical Clinical Pathways Complement Cytometry Data Endothelium Feedback Fingerprint Flow Cytometry Gene Expression Profile Genes Genetic Transcription Goals Hematopoietic Heterogeneity Homeostasis Human Immunity Immunologic Receptors Infection Inflammation Inflammatory Injury Interruption Intervention LOX gene Learning Lectin Lectin Receptors Leukocytes Ligands Lipids Low Density Lipoprotein Receptor Lower Respiratory Tract Infection Lung Lung infections Membrane Proteins Messenger RNA Morbidity - disease rate Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Neutrophil Infiltration Outcome PPAR gamma Patient-Focused Outcomes Patients Pilot Projects Pneumonia Population Proteins Public Health Pulmonary Inflammation RXR Respiratory Tract Infections Risk Role Sepsis Shapes Signal Transduction Site Source Specimen System Testing Tissues Vascular Endothelium Viral alveolar homeostasis base disorder risk fortification granulocyte immunopathology in vivo lung injury macrophage mortality neutrophil novel oxidized low density lipoprotein programs protective effect protein expression receptor recruit resilience response scavenger receptor selective expression sepsis induced ARDS single-cell RNA sequencing tissue injury vascular injury virtual

项目摘要

Abstract Pneumonia is a leading cause of morbidity and mortality worldwide, due in large part to the onset of acute respiratory distress syndrome (ARDS), for which there is no greater origin. Imbalances of the biological processes controlling immunity and tissue integrity increase the likelihood that lung infections progress to pneumonia, demanding a better understanding of when, where, and how host signals integrate to confer protection. Here we propose the scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) as a regulatory node for shaping inflammation in the pneumonic lung. While this receptor has well- established roles in promoting vascular injury in patients with atherosclerosis, its function in the lungs is unknown. Our preliminary results from both mice and humans indicate substantial accumulation of LOX-1 in pneumonic lungs. Moreover, our mouse studies reveal that LOX-1 in the airspace compartment, particularly that originating from hematopoietic cells, dampens immunopathology in the infected lung. This contrasts the harmful roles of LOX-1 during cardiovascular disease, implicating the alveolar milieu as a unique niche for LOX-1-dependent tissue fortification. Although LOX-1 has never been investigated in the context of lung infections, we posit that its expression by alveolar macrophages and neutrophils serves as a countermeasure to dampen pneumonia-induced inflammation and maintain tissue integrity. Therefore, we will test the central hypothesis that LOX-1 on airspace myeloid cells bolsters tissue protection in response to lung infection. This will be addressed by pursuing the following 3 aims: Aim 1) Test the hypothesis hematopoietic cellular subsets prominently contribute to LOX-1-driven tissue protection in the infected lung; Aim 2) Test the hypothesis that LOX-1 promotes efferocytosis and repolarization in alveolar macrophages to limit immunopathology during pneumonia; and Aim 3) Test the hypothesis that LOX-1 guides alveolar neutrophils towards an MDSC-like state through altered lipid handling and anti-inflammatory feedback, countering infection-induced injury. Our proposed studies will leverage complementary in vivo and ex vivo approaches in order to reveal basic biological mechanisms of tissue homeostasis during pneumonia, paving the way for novel clinical interventions in patients with or at risk for this disease.

抽象的肺炎是全世界发病和死亡的主要原因，很大程度上是由于急性发作呼吸窘迫综合征（ARDS），没有更大的起源。生物体失衡控制免疫和组织完整性的过程增加了肺部感染进展为肺炎，需要更好地了解宿主信号何时、何地以及如何整合以赋予保护。这里我们提出了清道夫受体凝集素样氧化低密度脂蛋白受体-1 (LOX-1) 作为调节肺炎症的调节节点。虽然这种受体具有良好的已确定其在促进动脉粥样硬化患者血管损伤方面的作用，其在肺中的功能是未知。我们对小鼠和人类的初步结果表明，LOX-1 在体内大量积累。肺脏。此外，我们的小鼠研究表明，LOX-1 在空域隔间中，特别是源自造血细胞的病毒会抑制受感染肺部的免疫病理学。这对比了 LOX-1 在心血管疾病中的有害作用，表明肺泡环境是一个独特的生态位 LOX-1 依赖性组织强化。尽管 LOX-1 从未在肺环境中进行过研究感染，我们假设肺泡巨噬细胞和中性粒细胞表达它作为一种对策抑制肺炎引起的炎症并保持组织完整性。因此，我们将测试中央假设空腔髓样细胞上的 LOX-1 可增强组织保护以应对肺部感染。这将通过追求以下 3 个目标来解决：目标 1) 检验造血细胞亚群的假设显着促进 LOX-1 驱动的受感染肺部组织保护；目标 2) 检验假设 LOX-1 促进肺泡巨噬细胞的胞吞作用和复极化，以限制免疫病理学肺炎;目标 3) 检验 LOX-1 引导肺泡中性粒细胞向 MDSC 样方向发展的假设通过改变脂质处理和抗炎反馈来抵抗感染引起的损伤。我们的拟议的研究将利用互补的体内和离体方法来揭示基本的肺炎期间组织稳态的生物学机制，为新型临床干预措施铺平道路患有这种疾病或有患这种疾病风险的患者。