Quercetin prevents progression of COPD lung disease by modulating Foxo3Aactivity

槲皮素通过调节 Foxo3A 活性预防 COPD 肺部疾病的进展

• 批准号: 9543962
• 负责人: Umadevi Sivanappa Sajjan
• 金额: $ 41.88万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9543962
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acetylation; Affect; Airway Disease; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apple; Attenuated; Autophagocytosis; Autophagosome; Berry; Binding; Biological Process; Cause of Death; Cell Culture Techniques; Cell Nucleus; Cells; Characteristics; Chronic Obstructive Airway Disease; DNA Binding; Data; Deacetylase; Diet; Disease; Disease Outcome; Disease model; Dose; E-Cadherin; EGF gene; EP300 gene; Elastases; Epidermal Growth Factor Receptor; Epithelial Cells; FOXO3A gene; Flavanol; Flavonoids; Food; Genes; Genetic Transcription; Goals; Goblet Cells; Human; IL8 gene; In Vitro; Infection; Inflammation; Inflammatory; Ligands; Lung; Lung Inflammation; Lung diseases; Matrix Metalloproteinases; Medicine; Metaplasia; Modeling; Molecular; Monitor; Mucins; Mucous body substance; Mus; Nuclear; Nuclear Translocation; Onions; Outcome; Oxidative Stress; Patients; Phase; Phenotype; Phosphorylation; Phosphotransferases; Pilot Projects; Plants; Predisposition; Process; Property; Protein Phosphatase 2A Regulatory Subunit PR53; Publishing; Pulmonary Emphysema; Quercetin; Resistance; Respiratory physiology; Rhinovirus; SIRT1 gene; Surface; Testing; Transactivation; Viral; Viral Load result; Virus Replication; airway epithelium; airway inflammation; antioxidant enzyme; base; chemokine; cytokine; genetic inhibitor; improved; in vitro Model; in vivo; inhibitor/antagonist; insight; knock-down; mouse model; overexpression; p300/CBP-Associated Factor; preclinical study; prevent; promoter; public health relevance; restoration; transcription factor

DESCRIPTION (provided by applicant): Project Summary Quercetin, a plant flavonoid is a potent antioxidant and anti-inflammatory agent. We have performed preclinical studies assessing the suitability of quercetin in the treatment of chronic obstructive pulmonary disease (COPD), a third leading cause of death in the U.S. We showed that quercetin reduces lung inflammation, goblet cell metaplasia and progression of emphysema, in part by increasing expression of the deacetylase Sirt1 in elastase/LPS-exposed mice displaying typical features of COPD. Our pilot studies indicate that elastase/LPS-exposed mice show reduced nuclear FOXO3a, a transcription factor that negatively regulates inflammation and provide resistance to oxidative stress. Further, we found that COPD airway epithelial cells which maintain the phenotypic characteristics of the COPD airway epithelium also show reduced nuclear levels of Sirt1 as well as FOXO3a. Infection with human rhinovirus (RV), a common cause of COPD exacerbations further reduced nuclear Sirt1 and FOXO3a levels. Our pilot studies also show that quercetin promotes translocation of FOXO3a to the nucleus in elastase/LPS-treated mice. Further, quercetin treatment of COPD epithelial cell cultures reduced IL-8 expression and mucus metaplasia, while restoring nuclear FOXO3a levels. Finally, quercetin improved viral clearance after RV challenge in both elastase/LPS mice and COPD epithelial cells. The overall goal is to elucidate the mechanisms by which quercetin modulates nuclear FOXO3a and Sirt1 levels, thereby decreasing inflammation, goblet cell metaplasia and augment viral clearance in COPD models. To accomplish this goal, we propose the following specific Aims. 1. Determine the mechanisms by which quercetin modulates FOXO3a activity and inhibits overexpression of IL-8 and other chemokines and reduces lung inflammation in COPD models. Nuclear translocation of FOXO3a is regulated by phosphorylation and acetylation. We test the hypotheses that 1) quercetin treatment blocks Akt kinase activity, thereby increasing FOXO3A translocation to the nucleus; 2) quercetin-induced Sirt1 deacetylates nuclear FOXO3a, preventing phosphorylation by Akt export from the nucleus; and 3) Sirt1 and FOXO3a together block NF-κB binding to the CXCL-1, 2, 5 and 8 promoter, thereby attenuating cytokine expression and lung inflammation. 2. Examine the mechanisms by which quercetin decreases goblet cell metaplasia in COPD airways. Our pilot data indicate aberrant activation of EGFR in COPD cells as well as in COPD mouse model. We will test the hypotheses that 1) quercetin-induced nuclear FOXO3a positively regulates expression of E-cadherin, which sequesters EGFR at the epithelial cell basolateral surface; 2) quercetin directly inhibits EGFR activity; 3) quercetin, by restoring Sirt1 levels, inhibits matrix metalloproteinase (MMP) expression, thereby decreasing the availability of EGF ligands; and 4) reduced EGFR activity decreases expression of mucin genes, preventing goblet cell metaplasia. 3. Determine the mechanisms by which quercetin increases viral clearance in COPD airways. COPD exacerbations are associated with increased oxidative stress We will test the hypotheses that: 1) oxidative stress induces formation and accumulation of autophagosomes, providing a platform for viral replication; 2) RV infection, via its effects on Akt and CBP/p300, decreases nuclear FOXO3a and phase II antioxidant enzyme expression, amplifying derangements present in COPD cells; and 3) quercetin restores antioxidant enzyme expression by modulation of FOXO3a and Sirt1, decreasing autophagy and increasing viral clearance. Completion of these studies will provide important insights into mechanisms by which quercetin decreases airway inflammation, goblet cell metaplasia and viral clearance in chronic obstructive lung disease. These studies are required to determine the suitability of quercetin as an alternative complimentary medicine in the management of COPD lung disease.

描述（应用程序提供）：植物类黄酮的项目摘要槲皮素是潜在的抗氧化剂和抗炎剂。 We have performed preclinical studies assessing the suitability of quercetin in the treatment of chronic obstructive pulmonary disease (COPD), a third leading cause of death in the U.S. We showed that quercetin reduces lung infection, goblet cell metaplasia and progression of emphysema, in part by increasing expression of The deacetylase Sirt1 in elastase/LPS-exposed mice displaying typical features of COPD.我们的试点研究表明，弹性酶/LPS暴露的小鼠显示核FOXO3A降低，核FOXO3A是一种负调节感染并提供对氧化物胁迫的抗性的转录因子。此外，我们发现维持COPD气道上皮的表型特征的COPD气道上皮细胞也显示出SIRT1和FOXO3A的核水平降低。人类鼻病毒（RV）感染，COPD加剧的常见原因进一步降低了核SIRT1和FOXO3A水平。我们的试点研究还表明，槲皮素促进了FOXO3A在弹性酶/LPS处理的小鼠中的翻译。此外，槲皮素治疗COPD上皮细胞培养物可降低IL-8的表达和粘液化生，同时恢复核FOXO3A水平。最后，在弹性酶/LPS小鼠和COPD上皮细胞中，槲皮素改善了RV挑战后的病毒清除率。总体目标是阐明槲皮素调节核FOXO3A和SIRT1水平的机制，从而降低注射，杯状细胞过失和COPD模型中的增强病毒清除率。为了实现这一目标，我们提出以下特定目标。 1。确定槲皮素调节FOXO3A活性并抑制IL-8和其他趋化因子的过表达并减少COPD模型中的肺部感染的机制。 FOXO3A的核易位受磷酸化和乙酰化的调节。我们测试了1）槲皮素治疗阻断Akt激酶活性的假设，从而增加了FOXO3A的易位； 2）槲皮素诱导的sirt1脱乙酰基核FOXO3A，可防止Akt从核中导出的磷酸化； 3）SIRT1和FOXO3A共同阻断NF-κB与CXCL-1、2、5和8启动子结合，从而减弱了细胞因子表达和肺部注射。 2。检查槲皮素在COPD气道中降低杯状细胞化生的机制。我们的试点数据表明COPD细胞以及COPD小鼠模型中EGFR的异常激活。我们将测试以下假设：1）槲皮素诱导的FOXO3A 3。确定槲皮素通过恢复SIRT1水平抑制基质金属蛋白酶（MMP）的表达的机制，从而降低了EGF配体的可用性； 4）降低的EGFR活性降低了粘蛋白基因的表达，从而阻止了杯状细胞化生。 3。确定槲皮素在COPD气道中增加病毒清除率的机制。 COPD加剧与增加的氧化应激有关，我们将测试以下假设：1）氧化应激会诱导自噬体的形成和积累，为病毒复制提供平台； 2）RV感染通过其对AKT和CBP/P300的影响，降低了核FOXO3A和II期抗氧化剂酶的表达，从而扩大了COPD细胞中存在的进化； 3）槲皮素通过调节FOXO3A和SIRT1恢复抗氧化剂酶的表达，减少自噬并增加病毒清除率。这些研究的完成将提供有关槲皮素减少气道感染，杯状细胞变质和病毒清除率的机制的重要见解。需要这些研究来确定槲皮素作为在COPD肺部疾病管理中的替代免费医学的适用性。

项目成果

Rhinovirus and COPD airway epithelium.

• DOI: 10.15761/pccm.1000139
• 发表时间: 2017-10
• 期刊: Pulmonary and critical care medicine
• 作者: Owuor N;Nalamala N;Gimenes JA Jr;Sajjan US
• 通讯作者: Sajjan US

Rhinovirus-induces progression of lung disease in a mouse model of COPD via IL-33/ST2 signaling axis.

• DOI: 10.1042/cs20181088
• 发表时间: 2019-04-30
• 期刊: Clinical science (London, England : 1979)

Microarray analysis identifies defects in regenerative and immune response pathways in COPD airway basal cells.

微阵列分析可识别慢性阻塞性肺病气道基底细胞再生和免疫反应途径的缺陷。

• DOI: 10.1183/23120541.00656-2020
• 发表时间: 2020
• 期刊: ERJ open research
• 影响因子: 4.6
• 作者: Pineau,Fanny;Shumyatsky,Gabriella;Owuor,Nicole;Nalamala,Nisha;Kotnala,Sudhir;Bolla,Sudhir;Marchetti,Nathaniel;Kelsen,Steven;Criner,GerardJ;Sajjan,UmaS
• 通讯作者: Sajjan,UmaS