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.

项目总结：糖皮质激素在炎症的治疗中是不可缺少的，尽管它们不是