The role of Lox-1 during pneumonia

Lox-1 在肺炎中的作用

基本信息

批准号：
9758949
负责人：
Filiz Korkmaz
金额：
$ 6.12万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9758949
关键词：
Acute Acute Lung Injury Address Adult Respiratory Distress Syndrome Advanced Glycosylation End Products Affect Anti-inflammatory Antibiotics Antibodies Antimicrobial Resistance Atherosclerosis Bacterial Pneumonia Biological Biology Blood Platelets Bone Marrow Bronchoalveolar Lavage Fluid Cell surface Cells Cessation of life Chimera organism Clinical Complement Development Endothelium Epithelial Cells Escherichia coli Etiology Fostering Future Gene Expression Profiling Generations Genetic Transcription Goals Gram-Negative Bacteria Hematopoietic Heterogeneity Homeostasis Immune Immune response Immunity In Vitro Infection Inflammation Inflammatory Injury Intervention Invaded Investigation Irrigation Knockout Mice Knowledge LOX gene Lead Lectin Leukocytes Life Ligands Liquid substance Low Density Lipoprotein Receptor Lung Lung infections Measures Mediating Mediator of activation protein Membrane Mind Morbidity - disease rate Mus Neutrophil Infiltration Outcome Pathway interactions Patients Pharmacology Pneumonia Process Public Health Pulmonary Inflammation Recombinants Recovery Regulation Research Risk Role Source Surface Techniques Testing Time Tissues Training Programs career experimental study genetic approach immune resistance insight lung injury macrophage microbial mortality neutrophil novel oxidized low density lipoprotein pathogen receptor recruit resilience response scavenger receptor therapy development vascular inflammation

项目摘要

Abstract Lung infections are a major contributor to the worldwide public health burden, resulting in significant morbidity and mortality, the latter of which has not improved since the discovery of antibiotics. Successful recovery from pneumonia requires both host immune resistance and tissue resilience, the latter of which serves to counter damage elicited by the invading pathogen or the host itself. At present, there is a major knowledge gap regarding the biological pathways controlling lung resilience that lead to either successful recovery or the development of pneumonia-related complications such as ARDS. Here we propose Lectin-like oxidized low- density lipoprotein receptor-1 (LOX-1) as a potential mediator of acute pulmonary inflammation and tissue homeostasis during pneumonia. LOX-1 is a class E scavenger receptor that responds to multiple inflammatory ligands including oxLDL, advanced glycation end products, and activated platelets, and is primarily known for its role in promoting endothelial inflammation in the setting of atherosclerosis. Our preliminary results show for the first time that both membrane-bound LOX-1 and its soluble, potentially anti-inflammatory counterpart (sLOX-1) are markedly increased at the transcriptional and translational level in response to pneumonia caused by Gram-negative bacteria. LOX-1 also decreases on the cell surface of lung-recruited neutrophils, and this occurs concomitantly with a significant increase in sLOX-1 recovered from pneumonic airspaces. Interestingly and contrary to known prototypical inflammatory role of LOX-1, we have found that antibody- mediated inhibition of lung LOX-1 in the airspaces, results in exaggerated tissue injury and inflammation following E. coli pneumonia, with no effect on bacterial clearance or leukocyte recruitment. This discovery reveals a novel, tissue-protective role for intra-pulmonary LOX-1 during pneumonia, potentially mediated by neutrophil delivery of soluble LOX-1 to the airways. However, the sources, targets, and biological significance of pulmonary LOX-1 are currently unknown. Thus, we propose the central hypothesis that neutrophils deliver LOX-1 to pneumonic airspaces in order to limit inflammatory tissue injury. This hypothesis will be tested by pursuing the following aims: 1) To elucidate the primary sources of pulmonary LOX-1 and its influence on lung injury during pneumonia; and 2) To test the hypothesis that neutrophil-derived soluble LOX-1 mitigates acute pulmonary inflammation. Results from our investigations will be the first to reveal when, whether, and why lung LOX-1 impacts pneumonia outcome, perhaps paving the way for novel clinical interventions in at risk patients.

抽象的肺部感染是全球公共卫生负担的一个主要原因，导致发病率很高和死亡率，自从抗生素发现以来，后者的死亡率并没有改善。成功恢复自肺炎需要宿主免疫抵抗力和组织弹性，后者可以对抗由入侵的病原体或宿主本身引起的损害。目前，存在重大知识差距关于控制肺恢复能力的生物途径，这些途径导致成功康复或肺炎相关并发症（如 ARDS）的发生。在这里，我们提出类凝集素氧化低密度脂蛋白受体 1 (LOX-1) 作为急性肺部炎症和组织的潜在介质肺炎期间的体内平衡。 LOX-1是一种E类清道夫受体，可响应多种炎症配体，包括 oxLDL、晚期糖基化终末产物和活化血小板，主要以它在动脉粥样硬化中促进内皮炎症的作用。我们的初步结果显示首次发现膜结合 LOX-1 及其可溶性、潜在抗炎对应物 (sLOX-1) 在转录和翻译水平上显着增加以应对肺炎由革兰氏阴性菌引起。 LOX-1 在肺招募的中性粒细胞的细胞表面也减少，并且这与从肺空域回收的 sLOX-1 显着增加同时发生。有趣的是，与 LOX-1 已知的典型炎症作用相反，我们发现抗体- 介导的肺 LOX-1 在空腔中的抑制，导致组织损伤和炎症过度大肠杆菌肺炎后，对细菌清除或白细胞募集没有影响。这一发现揭示了肺炎期间肺内 LOX-1 的一种新的组织保护作用，可能是由中性粒细胞将可溶性 LOX-1 输送至气道。然而，其来源、目标和生物学意义肺 LOX-1 的作用目前尚不清楚。因此，我们提出中性粒细胞传递的中心假设 LOX-1 进入肺泡以限制炎症组织损伤。这个假设将被检验追求以下目标：1）阐明肺LOX-1的主要来源及其对肺的影响肺炎期间受伤； 2) 检验中性粒细胞来源的可溶性 LOX-1 减轻急性肺部炎症。我们的调查结果将首先揭示何时、是否以及为何肺 LOX-1 影响肺炎结局，或许为高危患者的新型临床干预措施铺平道路。