The role of Lox-1 during pneumonia

Lox-1 在肺炎中的作用

• 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
• 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

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.

摘要 肺部感染是全球公共卫生负担的主要来源，导致显著的发病率 和死亡率，后者自抗生素发现以来一直没有改善。成功从 肺炎需要宿主免疫抵抗力和组织弹性，后者用于对抗 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 关于控制肺弹性的生物途径，导致成功恢复或 发生肺炎相关并发症，如ARDS。在这里，我们提出凝集素样氧化低- 密度脂蛋白受体-1（LOX-1）作为急性肺部炎症和组织炎症的潜在介质 肺炎期间的体内平衡LOX-1是一种E类清道夫受体，其响应于多种炎症反应。 配体，包括oxLDL、晚期糖基化终产物和活化血小板，并且主要已知 其在动脉粥样硬化背景下促进内皮炎症的作用。初步结果显示， 这是第一次，膜结合的LOX-1和它的可溶性，潜在的抗炎对应物 在肺炎时，sLOX-1在转录和翻译水平上显著增加 由革兰氏阴性细菌引起。LOX-1在肺募集的中性粒细胞的细胞表面上也减少， 这伴随着从肺炎气隙中回收的sLOX-1的显著增加而发生。 有趣的是，与已知的LOX-1的典型炎症作用相反，我们发现抗体- 介导的肺LOX-1在空气空间中的抑制，导致过度的组织损伤和炎症 继E.大肠杆菌肺炎，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，可能由 嗜中性粒细胞将可溶性LOX-1递送至气道。然而，来源，目标和生物学意义 肺LOX-1目前尚不清楚。因此，我们提出了一个中心假设，即中性粒细胞 L0 X-1至肺部空气空间以限制炎性组织损伤。这一假设将由以下人员进行检验： 目的：1）阐明肺LOX-1的主要来源及其对肺组织的影响 肺炎期间的损伤;和2）为了检验嗜中性粒细胞衍生的可溶性LOX-1减轻急性损伤的假设， 肺部炎症从我们的调查结果将首先揭示何时，是否，以及为什么肺 LOX-1影响肺炎预后，可能为高危患者的新型临床干预铺平道路。