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

基本信息

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
项目类别：
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

项目摘要

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.

促炎基因和抗炎基因转录的平衡对于正常机体至关重要脓毒症组织损伤后体内平衡的异常调节达到顶峰。在不受控制的全身炎症中，导致肺组织损伤和水肿，呼吸道然而，病理性炎症的确切机制。对脓毒症的了解甚少，因此加速解决脓毒症的策略是该提案中的研究将检验致病信号传导的新假设。脓毒症引起的原因是巨噬细胞特异性 Fra-1/AP-1 限制性表达抗- 炎症 A20，一种重要的泛素编辑酶，可终止 NF-失控的激活我们使用三种脓毒症临床前模型进行了 κB 和 MAP 激酶信号传导。表明 Fra-1 是脓毒症促炎症反应的重要介质。 (LPS) 和肺炎假单胞菌引起的肺损伤和炎症在 Fra-1 缺陷小鼠与遭受伤害剂量的 Fra-1 缺陷小鼠相比。与野生型相比，i.t细菌内毒素（LPS）显示出肺损伤的加速消退我们发现 Fra-1 的表达主要在尸体肺的肺泡巨噬细胞中增加。离体感染大肠杆菌和暴露于 LPS 的小鼠重要的是，骨髓中缺乏 Fra-1 的小鼠。初步研究表明，在感染性休克和多种微生物败血症中，细胞比野生型小鼠存活时间更长。研究中，我们发现 LPS 诱导的 NF-κB 激活水平降低，并且人类和小鼠中 Fra-1 缺陷型巨噬细胞中的 A20 单倍体充足性相关。我们将解决以下具体假设：慢性或病理性脓毒症环境中继发于微生物损伤的 Fra-1 激活受到限制最佳 A20 表达并触发促炎反应，从而损害细胞的分辨率我们将使用生理和分子方法以及组织特异性基因敲除小鼠和测试这一假设的脓毒症临床前模型该提案的具体目标是：1) 确定巨噬细胞特异性 Fra-1 信号传导在介导中的作用和机制假单胞菌肺炎和脓毒症中的持续性肺损伤，以及 2) 通过以下方式检查其机制其中 Fra-1 通过巨噬细胞中的微生物损伤限制 A20 转录诱导，并且确定 Fra-1 限制的 A20 信号是持续性肺损伤的致病因素拟议的研究将确定加速肺脓毒症治疗的新见解和目标。假单胞菌肺炎和败血症患者的损伤修复。