Mechanisms Of Impaired Macrophage Function in Lung Injury - Project 4

肺损伤中巨噬细胞功能受损的机制 - 项目 4

• 批准号: 10204083
• 负责人: Janet Sojung Lee
• 金额: $ 36.74万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-03 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204083
• 关键词: Acids; Aconitic Acid; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Alternative Complement Pathway; Anemia due to Chronic Disorder; Antiviral Agents; Automobile Driving; Bacterial Pneumonia; CRISPR/Cas technology; CXCL10 gene; Carboxy-Lyases; Complement; Complement Activation; Complement Factor B; Complication; Critical Illness; Data; Decarboxylation; Defect; Erythrocytes; Exhibits; Failure; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Health Care Costs; Host Defense; Human; IRF1 gene; Immunosuppression; Impairment; In Vitro; Infection; Interferons; Intervention; Ions; Klebsiella pneumoniae; Kupffer Cells; Length of Stay; Link; Liver; Lower Respiratory Tract Infection; Lung; Lung infections; Mechanical ventilation; Mediating; Medical; Mitochondria; Modeling; Molecular; Mononuclear; Morbidity - disease rate; Mus; Natural Immunity; Natural Killer Cells; Nosocomial pneumonia; Oxides; Pathway interactions; Patients; Phagocytes; Phenotype; Physiological; Pneumonia; Prevalence; Production; Reactive Oxygen Species; Risk; Risk Factors; Sepsis; Serum; Shock; Signal Transduction; Site; Stress; Supporting Cell; System; T-Lymphocyte; Testing; Transactivation; Transfusion; antimicrobial; bactericide; chemokine; cohort; complement deficiency; cytokine; extracellular; in vivo; lung injury; macrophage; microbial; monocyte; mouse model; novel; pathogen; patient population; physiologic stressor; programs; recruit; response; transcription factor

Project Summary/Abstract: The broad, long-term objective of this Project is to better understand the underlying mechanisms of immunosuppression following infection in the lungs by examining distinct host- pathogen interplay. Severe acute lower respiratory tract infection or pneumonia remains a major cause of sepsis and risk factor for the acute respiratory distress syndrome (ARDS) worldwide. However, bacterial pneumonia is also a frequent complication of ARDS and prolonged mechanical ventilation that increases patient morbidity, length of stay, and health-care costs. Yet, many aspects of host-pathogen interactions remain poorly understood and the underlying defects in host control mechanisms that occur during critical illness remain outstanding questions in ARDS. We have developed a 2-hit murine model targeting the mononuclear phagocyte system of the liver to study the consequences of severe lung infection induced by Klebsiella pneumoniae, an extracellular Gram-negative pathogen that is a common cause of nosocomial pneumonia, and potential link to systemic immunosuppression. We identified impaired expression of interferon- regulatory factor 1 (IRF-1), a transcription factor critical for boosting antimicrobial and antiviral innate immunity, in this 2-hit model leading us to propose that defects in IRF-1 mediates the immunosuppressive phenotype by impairing transactivation of key innate immunity genes important for host defense. Moreover, preliminary findings suggest that a proportion of critically ill patients exhibit an immunosuppressive phenotype characterized by failure to control relatively avirulent carbapenamase-producing Klebsiella pneumoniae (KP) growth in vitro, and impaired serum killing of KP is associated with defects in alternative but not classical complement activity. Most complement proteins are synthesized in the liver, but macrophages/monocytes also synthesize these factors, many of which are regulated by interferons. Collectively, preliminary findings from the 2-hit model and patient serum have led us to propose a major hypothesis that macrophage dysfunction characterized by defects in IRF-1 marks the host for an immunosuppressive fate during infection due to impaired cytokine response, microbial killing, and complement activity. Aim 1 will determine whether impairment in IRF-1 signaling is a mechanism for defective chemokine and cytokine response in the 2-hit model. Aim 2 will evaluate whether defects in mitochondrial aconitate decarboxylase 1 (ACOD1) downstream of IRF-1 impairs host anti-microbial program during KP infection and in the 2-hit model. Aim 3 will evaluate IRF-1 activation, the dynamics of alternative pathway complement factors synthesized by mononuclear phagocytes, and relationship to AP activity in a cohort of critically ill patients. Successful completion of the aims will elucidate novel mechanisms of host control and aid in the long-term objective of understanding immunosuppressive signals complicating severe pneumonia.

项目摘要/摘要：该项目的广泛，长期目标是更好地了解 通过检查不同宿主 - 病原体相互作用。严重的急性下呼吸道感染或肺炎仍然是 全球急性呼吸遇险综合征（ARDS）的败血症和危险因素。但是，细菌 肺炎也是ARDS的常见并发症和延长的机械通气，增加了 患者发病率，住院时间和医疗保健费用。然而，宿主病原体相互作用的许多方面 保持不明的理解和临界期间发生的宿主控制机制中的潜在缺陷 疾病在ARDS中仍然是出色的问题。我们已经开发了一个针对的2次鼠模型 肝脏的单核吞噬细胞系统研究了由 肺炎克雷伯氏菌，一种细胞外革兰氏阴性病原体，是医院的常见原因 肺炎，以及与全身免疫抑制的潜在联系。我们确定了干扰素的表达受损 调节因子1（IRF-1），这是提高抗菌和抗病毒先天免疫的至关重要的转录因子， 在这种2次打击的模型中，我们提出了IRF-1中的缺陷会介导免疫抑制表型 关键先天免疫基因的反式激活对宿主防御很重要。而且，初步 调查结果表明，一定比例的重症患者表现出免疫抑制表型 其特征是无法控制相对无毒的碳纤维烯酶产生肺炎克雷伯氏菌（KP） 体外生长，KP的血清杀伤受损与替代方案的缺陷有关 补充活动。大多数补体蛋白在肝脏中合成，但巨噬细胞/单核细胞也是 合成这些因素，其中许多因素受干扰素调节。总的来说，从 2次打击模型和患者血清使我们提出了一个主要假设，即巨噬细胞功能障碍 IRF-1中缺陷的特征是在感染期间因免疫抑制命运的宿主。 细胞因子反应受损，微生物杀伤和补体活性。 AIM 1将确定是否 IRF-1信号传导中的损伤是一种缺陷趋化因子和细胞因子反应的机制 2击模型。 AIM 2将评估线粒体链氨酸脱羧酶1（ACOD1）中的缺陷是否存在 IRF-1的下游会损害KP感染期间和2 HIT模型中宿主抗微生物程序。目标3意志 评估IRF-1激活，替代途径补充因子合成的动力学 一系列重症患者中的单核吞噬细胞以及与AP活性的关系。成功的 目的的完成将阐明宿主控制的新型机制，并以长期目标的长期目标 了解免疫抑制信号使严重的肺炎复杂化。