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.

促炎和抗炎基因转录的平衡对于正常的 脓毒性组织损伤后的内环境稳定。这种转录平衡的异常调节 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。然而，病理性炎症的确切机制 在脓毒症中的作用知之甚少，因此加速脓毒症消退的策略是 非常有限。该提案中的研究将测试致病信号传导的新假设， 脓毒症引起的巨噬细胞特异性Fra-1/AP-1限制性表达抗- 炎症A20，一种关键的泛素编辑酶，终止NF-κ B的不受控制的激活。 κB和MAP激酶信号传导。我们的初步研究，使用三种败血症的临床前模型， 表明Fra-1是脓毒症中促炎反应的重要介质。内毒素 （LPS）和假性肺炎诱导的肺损伤和炎症在 Fra-1缺陷小鼠比野生型小鼠。Fra-1缺陷小鼠接受损伤剂量的 i.t细菌内毒素（LPS），与野生型相比，显示出肺损伤的加速消退 小鼠我们发现尸体肺肺泡巨噬细胞中Fra-1的表达增加 感染了大肠大肠杆菌离体和暴露于LPS的小鼠中。重要的是，在骨髓中缺乏Fra-1的小鼠 细胞比野生型小鼠在败血性休克和多微生物败血症中存活更长时间。初步 研究中，我们发现LPS诱导的NF-κB活化水平降低， Fra-1缺陷型巨噬细胞中的A20。人类和小鼠中的A20单倍充足性与 全身炎症加剧我们将讨论的具体假设，在 继发于微生物损伤的慢性或病理性脓毒症Fra-1激活的情况限制了 最佳的A20表达，并触发促炎反应，从而削弱了分辨率 败血症我们将使用生理和分子方法和组织特异性敲除小鼠， 脓毒症的临床前模型来检验这一假设。该提案的具体目标是：1） 确定巨噬细胞特异性Fra-1信号转导在介导 假肺炎和脓毒症中的持续性肺损伤，以及2）通过以下方式检查机制： 其中Fra-1限制巨噬细胞中微生物损伤引起的A20转录诱导，以及 确定Fra-1限制的A20信号传导是持续性肺损伤的致病因素， 败血症拟议的研究将确定新的见解和治疗目标，以加速肺 假性肺炎和脓毒症患者的损伤修复。