Fra-1-A20 Signaling and Resolution of Pneumonia-Induced Sepsis

Fra-1-A20 信号传导和肺炎引起的败血症的解决

• 批准号: 9906946
• 负责人: Sekhar P. Reddy
• 金额: $ 30.78万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906946
• 关键词: Address; Alveolar Macrophages; Anti-Inflammatory Agents; Antigens; Binding; Bone Marrow; Cadaver; Cessation of life; Chimera organism; Chronic; Data; Dose; Edema; Endotoxemia; Endotoxins; Enzymes; Equilibrium; Escherichia coli; Exposure to; FOSL1 gene; Fos-Related Antigens; Gene Expression; Genetic Transcription; Heterodimerization; Homeostasis; Human; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Knock-out; Knockout Mice; Lead; Light; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Pathogenicity; Pathologic; Patients; Phenotype; Physiological; Pneumonia; Pre-Clinical Model; Process; Proteins; Pseudomonas; Regulation; Resolution; Respiratory Failure; Role; Secondary to; Sepsis; Septic Shock; Signal Transduction; Structure of parenchyma of lung; Testing; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Ubiquitin; Wild Type Mouse; bZIP Domain; base; cecal ligation puncture; injury and repair; insight; jun Oncogene; lung injury; lung repair; macrophage; microbial; mortality; mouse model; novel; polymicrobial sepsis; promoter; repaired; response; response to injury; septic; targeted treatment; tissue injury; tissue repair; transcription factor

The counter balancing of pro- and anti-inflammatory gene transcription is crucial for normal homeostasis after septic tissue injury. Aberrant regulation of this transcriptional balance culminates in an unchecked systemic inflammation, leading to lung tissue damage and edema, respiratory failure and ultimately death. However, the exact mechanisms underlying pathological inflammation in sepsis are poorly understood, and thus the strategies to accelerate the resolution of sepsis are very limited. Studies in the proposal will test the novel hypothesis that pathogenic signaling caused by sepsis is the result of a macrophage-specific Fra-1/AP-1 restricted expression of anti- inflammatory A20, a crucial ubiquitin-editing enzyme that terminates uncontrolled activation of NF- κB and MAP kinase signaling. Our preliminary studies, using three pre-clinical models of sepsis, showed that Fra-1 as a crucial mediator of pro-inflammatory responses in sepsis. Endotoxemia (LPS)- and pseudomonas pneumonia-induced lung injury and inflammation are markedly lower in Fra-1-deficient mice than wild-type counterparts. Fra-1-deficient mice subjected to injurious dose of i.t bacterial endotoxin (LPS), showed an accelerated resolution of lung injury compared to wild-type mice. We found increased expression of Fra-1 largely in alveolar macrophages of cadaveric lungs infected with E. coli ex vivo and in mice exposed to LPS. Importantly, mice lacking Fra-1 in myeloid cells survived longer than wild-type mice from septic shock and polymicrobial sepsis. In preliminary studies, we found reduced levels of LPS-induced NF-κB activation and an increased expression of A20 in Fra-1-deficient macrophages. A20 haplo-sufficiency in humans and in mice is associated with heightened levels of systemic inflammation. We will address the specific hypothesis that in the settings of chronic or pathological sepsis Fra-1 activation secondary to microbial insults restricts optimal A20 expression and triggers pro-inflammatory response, thereby impairing the resolution of sepsis. We will use physiological and molecular approaches and tissue-specific knockout mice and preclinical models of sepsis to test this hypothesis. The specific aims of the proposal are to: 1) Determine the role and mechanisms of macrophage-specific Fra-1 signaling in mediating sustained lung injury in pseudomonas pneumonia and sepsis, and 2) Examine the mechanisms by which Fra-1 restricts A20 transcriptional induction by microbial insults in macrophages, and determine that Fra-1 restricted A20 signaling is a causative factor of persistent lung injury in sepsis. The proposed studies will identify novel insights and targets for therapies to accelerate lung injury repair in patients with pseudomonas pneumonia and sepsis.

促疾病和抗炎基因转录的反平衡对于正常 化粪池损伤后的稳态。这种转录平衡的异常调节高潮 在未经检查的全身性炎症中，导致肺组织损伤和水肿，呼吸道 失败，最终死亡。但是，病理炎症的基本机制 在脓毒症中，人们了解得很熟悉，因此加速败血症的策略是 非常有限。该提案中的研究将检验致病信号的新假设 由败血症引起的是巨噬细胞特异性的FRA-1/AP-1抗抗 - 炎性A20，一种至关重要的泛素编辑酶，该酶终止了不受控制的NF-激活 κB和MAP激酶信号传导。我们的初步研究，使用三种链式链球运动模型， 表明FRA-1是败血症中促炎反应的关键介体。内毒素血症 （LPS） - 肺炎肺炎诱导的肺损伤和炎症明显较低 与野生型相比，FRA-1缺陷小鼠。 FRA-1缺陷小鼠遭受伤害剂量 I.T细菌内毒素（LPS），与野生型相比，肺损伤的分辨率加速了 老鼠。我们发现在尸体肺肺泡巨噬细胞中，FRA-1的表达增加了 感染了大肠杆菌的体内和暴露于LP的小鼠中。重要的是，髓样中缺乏FRA-1的老鼠 细胞的存活时间比败血性休克和多生物败血症的野生型小鼠的生存更长。在初步 研究，我们发现LPS诱导的NF-κB激活水平降低，并增加了 A20在FRA-1缺陷巨噬细胞中。人类和小鼠中的A20单plo充足率是相关的 随着全身炎症水平升高。我们将解决以下特定假设 继发于微生物侮辱的慢性或病理败血症的设置限制了 最佳A20表达和触发促炎反应，从而损害了分辨率 败血症。我们将使用物理和分子方法以及组织特异性的基因敲除小鼠， 败血症的临床前模型检验该假设。该提案的具体目的是：1） 确定巨噬细胞特异性FRA-1信号传导的作用和机制 肺炎和败血症患者持续肺损伤，以及2）检查机制 FRA-1通过微生物中的微生物侮辱限制了A20的转录诱导，并且 确定FRA-1限制A20信号传导是持续性肺损伤的病因 败血症。拟议的研究将确定疗法加速肺的新颖见解和靶标。 肺炎和败血症患者的损伤修复。