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; 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.

抽象的 肺部感染是全球公共卫生负担的主要贡献者，导致大量发病率 和死亡率，后者自发现抗生素以来就没有改善。成功恢复 肺炎既需要宿主的免疫耐药性和组织弹性，后者都需要反对 入侵病原体或宿主本身引起的损害。目前，有一个主要的知识差距 关于控制肺弹性的生物途径，导致成功恢复或 肺炎相关并发症（例如ARDS）的发展。在这里，我们提出了凝集素样氧化的低 - 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体 肺炎期间的稳态。 LOX-1是E类清除剂受体，对多种炎症做出反应 包括OXLDL，高级糖基化终产物和活化血小板在内的配体，主要以 它在动脉粥样硬化的环境中促进内皮炎症中的作用。我们的初步结果显示 膜结合的LOX-1及其可溶的，潜在的抗炎物 （Slox-1）在转录和翻译水平上明显增加，以应对肺炎 由革兰氏阴性细菌引起。 LOX-1在肺部核中嗜中性粒细胞的细胞表面也降低，并降低 这同时发生，从肺炎空间中回收的SLOX-1显着增加。 有趣的和与已知的lox-1原型炎症作用相反，我们发现抗体 - 介导的空间中肺Lox-1抑制作用，导致夸张的组织损伤和炎症 遵循大肠杆菌肺炎，对细菌清除或白细胞募集没有影响。这个发现 揭示了肺炎期间肺内LOX-1的新型组织保护作用，可能由 中性粒细胞向气道传递可溶性LOX-1。但是，来源，目标和生物学意义 目前尚不清楚肺Lox-1。因此，我们提出了中心粒细胞传递的中心假设 LOX-1至肺炎空间，以限制炎症组织损伤。该假设将通过 追求以下目的：1）阐明肺Lox-1的主要来源及其对肺的影响 肺炎时受伤； 2）检验中性粒细胞衍生的可溶性LOX-1减轻急性的假设 肺部炎症。我们的调查结果将是第一个揭示何时，肺的结果 LOX-1会影响肺炎结局，也许为AT风险患者的新型临床干预铺平了道路。