Glucocorticoid induced G-CSF in lung inflammation

糖皮质激素诱导 G-CSF 治疗肺部炎症

• 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
• 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

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.

项目摘要：糖皮质激素在炎症的治疗中是必不可少的 有效治疗严重哮喘和急性呼吸窘迫综合征中嗜中性肺部感染。 我们的长期目标是开发具有提高效率/风险比率的新糖皮质激素方案。目标 该建议是确定消除G-CSF信号是否会允许糖皮质激素促进 中性粒细胞凋亡和改善肺部感染。我们最近发现糖皮质激素 显着升高G-CSF，这是一种促进细胞因子的中性粒细胞。近年来G-CSF被认为是 耐肺炎症性疾病的原因。我们假设糖皮质激素保护中性粒细胞 通过刺激G-CSF来凋亡并增强中性粒细胞功能。 G-CSF诱导是由GR引发的 G-CSF启动子上的NF-BP50相互作用。肺中G-CSF产生的糖皮质激素诱导 居民细胞维持肺部注射。阻断G-CSF信号会提高糖皮质激素的效率 在规避嗜中性粒细胞驱动的肺注射中。为了检验我们的假设，我们将在体外检查系统 和体内。 AIM 1中的研究将检验GR和P50相互作用介导G-CSF表达的假设 在肺中的各种细胞类型中。 AIM 2中的研究将确定糖皮质激素诱导的G-CSF在 两种鼠模型中的中性粒细胞存活，功能，运输和中性粒细胞肺注射。我们将使用 阻止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 我们已经确定能够抑制G-CSF诱导的两个天然NF-B抑制剂：姜黄素和 parthenolide。我们的初步数据表明糖皮质激素受体（GR）和NF-B都需要 对于G-CSF诱导和P50而非P65，招募到G-CSF启动子的同一区域。 多个肺居民细胞和浸润白细胞在糖皮质激素刺激后产生G-CSF。 使用中和抗体阻止G-CSF信号传导，以取消糖皮质激素和IL-1β保护 嗜中性粒细胞因凋亡而产生。姜黄素与糖皮质激素结合减少了肺G-CSF，并且 LPS肺损伤模型中的中性粒细胞数。拟议的研究将提高我们对 糖皮质激素诱导的G-CSF在中性粒细胞糖皮质激素耐药性疾病中的作用。抑制g- 预计CSF信号传导会增加糖皮质激素抑制气道破坏的能力 中性粒细胞的活性和改善肺部感染。