Glucocorticoid induced G-CSF in lung inflammation

糖皮质激素诱导 G-CSF 治疗肺部炎症

基本信息

批准号：
9336499
负责人：
NICK LU
金额：
$ 39.13万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336499
关键词：
Acetylation Acute Lung Injury Adult Respiratory Distress Syndrome Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Apoptosis Asthma CSF3 gene Cells Colony-Stimulating Factor Receptors Curcumin DNA Polymerase II DNA Sequence Data Dimerization Disease Disease Resistance Epithelial Cells Event Genetic Transcription Glucocorticoid Receptor Glucocorticoids Goals Granulocyte-Macrophage Colony-Stimulating Factor IL8 gene In Situ Hybridization In Vitro Inflammation Inflammatory Interleukin-1 beta Interleukin-17 Knockout Mice Leukocytes Lung Lung Inflammation Mediating Mediator of activation protein Modeling Molecular Mus Neutrophilia Odds Ratio Osteocytes Partner in relationship Patients Pharmaceutical Preparations Pilot Projects Production Recruitment Activity Regimen Resistance Respiratory physiology Response Elements Role Signal Transduction Site Source Steroid Resistance Stimulus Structure of parenchyma of lung System T-Lymphocyte TNF gene TNFRSF5 gene Techniques Testing airway inflammation asthmatic cell type chemokine cytokine histone modification improved in vitro activity in vivo inhibitor/antagonist lung injury macrophage mouse model neutralizing antibody neutrophil novel therapeutic intervention p65 parthenolide promoter response trafficking

项目摘要

Project Summary: Glucocorticoids are indispensable in the treatment of inflammation although they are not effective in treating neutrophilic lung inflammation in severe asthma and acute respiratory distress syndrome. Our long-term goal is to develop new glucocorticoid regimens with improved efficacy/risk ratios. The goal of this proposal is to determine whether eliminating G-CSF signaling will allow glucocorticoids to promote neutrophil apoptosis and ameliorate lung inflammation. We have recently discovered that glucocorticoids significantly elevate G-CSF, a neutrophil promoting cytokine. G-CSF in recent years has been recognized as a cause of steroid-resistant lung inflammatory disorders. We hypothesize that glucocorticoids protect neutrophil from apoptosis and enhance neutrophil function via stimulation of G-CSF. G-CSF induction is initiated by GR and NF-B p50 interaction on the G-CSF promoter. Glucocorticoid-induction of G-CSF production in lung resident cells sustains lung inflammation. Blocking G-CSF signaling will increase the efficacy of glucocorticoids in circumventing neutrophil-driven lung inflammation. To test our hypotheses, we will examine systems in vitro and in vivo. Studies in Aim 1 will test the hypothesis that GR and p50 interactions mediate G-CSF expression in various cell types in lungs. Studies in Aim 2 will determine the role of glucocorticoid-induced G-CSF in neutrophil survival, functions, trafficking, and neutrophilic lung inflammation in two murine models. We will use three approaches to block G-CSF induction: using G-CSFR null mice, anti-G-CSF neutralizing antibodies, and two natural NF-B inhibitors that we have identified to be able to inhibit G-CSF-induction: curcumin and parthenolide. Our preliminary data indicate that both the glucocorticoid receptor (GR) and NF-B were required for G-CSF induction and p50, but not p65, was recruited to the same region of G-CSF promoter as GR. Multiple lung resident cells and infiltrating leukocytes produced G-CSF upon glucocorticoid stimulation. Blocking G-CSF signaling using neutralizing antibodies abolished glucocorticoid and IL-1β protection of neutrophils from undergoing apoptosis. Curcumin in combination with glucocorticoids reduced lung G-CSF and neutrophil numbers in an LPS lung injury model. The proposed studies will improve our understanding of the role of glucocorticoid-induced G-CSF in neutrophil-dominant glucocorticoid-resistant diseases. Inhibiting G- CSF signaling is anticipated to increase the ability of glucocorticoids to suppress the airway-damaging activities of neutrophils and ameliorate lung inflammation.

项目概要：糖皮质激素在炎症的治疗中是不可或缺的，尽管它们不是有效治疗严重哮喘和急性呼吸窘迫综合征的中性粒细胞性肺部炎症。我们的长期目标是开发新的糖皮质激素治疗方案，以提高疗效/风险比。该提案旨在确定消除 G-CSF 信号传导是否会让糖皮质激素促进我们最近发现糖皮质激素可以促进中性粒细胞凋亡并改善肺部炎症。显着升高G-CSF，近年来G-CSF已被公认为是一种促进中性粒细胞的细胞因子。我们勇敢地说糖皮质激素可以保护中性粒细胞。 GR 启动 G-CSF 诱导，防止细胞凋亡并增强中性粒细胞功能。和 NF-κB p50 对 G-CSF 启动子的相互作用，糖皮质激素诱导肺中 G-CSF 的产生。常驻细胞维持肺部炎症，阻断 G-CSF 信号传导将提高糖皮质激素的疗效。为了验证我们的假设，我们将在体外检查系统。目标 1 的研究将检验 GR 和 p50 相互作用介导 G-CSF 表达的假设。目标 2 中的研究将确定糖皮质激素诱导的 G-CSF 在肺部各种细胞类型中的作用。我们将使用两种小鼠模型中的中性粒细胞存活、功能、运输和中性粒细胞肺部炎症。阻断 G-CSF 诱导的三种方法：使用 G-CSFR 无效小鼠、抗 G-CSF 中和抗体和我们已鉴定出两种能够抑制 G-CSF 诱导的天然 NF-κB 抑制剂：姜黄素和我们的初步数据表明，糖皮质激素受体 (GR) 和 NF-κB 都是必需的。对于 G-CSF 诱导，p50（而非 p65）被招募到与 GR 相同的 G-CSF 启动子区域。多个肺驻留细胞和浸润白细胞在糖皮质激素刺激下产生 G-CSF。使用中和抗体阻断 G-CSF 信号传导消除了糖皮质激素和 IL-1β 的保护姜黄素与糖皮质激素联合使用可减少中性粒细胞凋亡。 LPS 肺损伤模型中的中性粒细胞数量。拟议的研究将提高我们对 LPS 肺损伤模型的理解。糖皮质激素诱导的 G-CSF 在抑制中性粒细胞为主的糖皮质激素耐药疾病中的作用。脑脊液信号传导有望增强糖皮质激素抑制气道损伤的能力中性粒细胞的活性并改善肺部炎症。