Inducible epithelial resilience during pneumonia

肺炎期间诱导上皮弹性

• 批准号: 9381339
• 负责人: Lee Quinton
• 金额: $ 41.13万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381339
• 关键词: Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Air; Alveolar; Antibiotic-resistant organism; Antimicrobial Resistance; Biological; Cell Death; Clinical; Communication; Complement; Data; Dependence; Development; Dichloromethylene Diphosphonate; Disease susceptibility; Endothelial Cells; Epithelial; Epithelial Cells; Epithelium; Escherichia coli; Etiology; Family; Floods; Genes; Genetic Transcription; Genotype; Goals; Homeostasis; Host Defense; Immune; Immunity; Infection; Injury; Interleukin-6; Interruption; Intervention; Invaded; Investigation; Kinetics; LIF gene; LOX gene; Laboratories; Liquid substance; Low Density Lipoprotein Receptor; Lung; Mediating; Mediator of activation protein; Microbe; Mononuclear; Morbidity - disease rate; Mus; Myeloid Cells; Outcome; Pathway interactions; Patients; Phagocytes; Pilot Projects; Pneumonia; Production; Property; Protein Dynamics; Proteins; Proteomics; Public Health; Publishing; Regulation; Research Design; Research Personnel; Risk; Sepsis; Severities; Severity of illness; Signal Transduction; Source; Staphylococcus aureus; Stimulus; Structure of parenchyma of lung; Testing; Tissues; Transcription Coactivator; antimicrobial; base; burden of illness; cell injury; cytokine; desensitization; experience; immune resistance; improved; in vivo; lung injury; macrophage; mortality; novel; paracrine; pathogen; prevent; receptor; resilience; response; socioeconomics; transcriptome

Abstract Pneumonia is a leading cause of morbidity and mortality across the socioeconomic spectrum. It is also the most frequent cause of acute respiratory distress syndrome (ARDS), due in large part to a harmful imbalance of biological pathways promoting antimicrobial resistance and tissue resilience. The latter is essential for maintaining barrier integrity and limiting alveolar flooding, but host mechanisms protecting the delicate air-liquid interface during pneumonia remain poorly understood. We have previously shown that the IL-6 family cytokine leukemia inhibitory factor (LIF) is critical for limiting acute lung injury in response to infection, and its protective properties do not appear to influence host immunity. A more complete understanding of the biological signals up- and downstream of this cytoprotective factor, which are currently unclear, may provide a unique and important window into pathways that dictate tissue homeostasis without compromising antimicrobial defense. Our published and preliminary results suggest that lung epithelium is both the source and target of LIF during pneumonia, serving as a mechanism of inducible resilience. Initial results also suggest that this response is macrophage-mediated, and that it may involve LIF-dependent changes in the cytoprotective transcriptional co- activator Yes-associated protein (YAP), as well as regulation of the low-density lipoprotein receptor-1 (LOX-1), which can promote injury and cell death. Here we propose the central hypothesis that epithelial integrity is maintained in pneumonic lungs by a macrophage-dependent paracrine LIF axis that promotes tissue resilience. This hypothesis will be tested by pursuing the following 3 aims: Aim 1) Test the hypothesis that LIFRβ signaling in lung epithelium prevents acute lung injury during pneumonia; Aim 2) Test the hypothesis that macrophage-epithelial communication initiates the tissue protective circuit mediated by LIF; and Aim 3) Test the hypothesis that LOX-1 induction sensitizes epithelial cells to pneumonic lung injury, and is countered by LIF to fortify tissue resilience. Studies designed to address these aims will employ complementary in vivo and ex vivo strategies to reveal novel pathways of tissue protection in the setting of lung infection. We anticipate that these findings will be leveraged for the development of novel clinical interventions in patients with or at risk for pneumonia and ARDS.

抽象的 肺炎是整个社会经济领域发病和死亡的主要原因。 急性呼吸窘迫综合征 (ARDS) 的最常见原因，很大程度上是由于有害的不平衡 促进抗菌素耐药性和组织弹性的生物途径的研究对于后者至关重要。 维持屏障完整性并限制肺泡溢流，但宿主机制保护脆弱的气液 我们之前已经表明，IL-6 家族细胞因子在肺炎期间的相互作用仍知之甚少。 白血病抑制因子（LIF）对于限制感染引起的急性肺损伤至关重要，其保护作用 特性似乎不会影响宿主免疫。对生物信号的更全面的了解。 目前尚不清楚该细胞保护因子的上下游，可能提供独特且 在不影响抗菌防御的情况下决定组织稳态的途径的重要窗口。 我们发表的初步结果表明，肺上皮既是 LIF 的来源又是目标。 肺炎，作为诱导弹性的机制，初步结果也表明这种反应是。 巨噬细胞介导的，并且它可能涉及细胞保护性转录共轭体中 LIF 依赖性的变化。 激活剂 Yes 相关蛋白 (YAP) 以及低密度脂蛋白受体 1 (LOX-1) 的调节， 它可以促进损伤和细胞死亡，在这里我们提出了上皮完整性的中心假设。 通过巨噬细胞依赖性旁分泌 LIF 轴维持在肺脏中，促进组织 该假设将通过追求以下 3 个目标进行检验： 目标 1) 检验以下假设： 肺上皮中的 LIFRβ 信号传导可预防肺炎期间的急性肺损伤；目标 2) 检验假设 巨噬细胞-上皮细胞通讯启动由 LIF 介导的组织保护回路；以及目标 3) 检验 LOX-1 诱导使上皮细胞对肺炎性肺损伤敏感的假设，并被反驳 通过 LIF 来增强组织弹性 旨在实现这些目标的研究将采用补充的体内方法。 以及离体策略，以揭示肺部感染情况下组织保护的新途径。 预计这些发现将被用于开发针对患者的新型临床干预措施 患有肺炎和 ARDS 或有患肺炎和 ARDS 的风险。