Quercetin prevent airway epithelial remodeling and promote lung health in OPD

槲皮素可预防 OPD 患者气道上皮重塑并促进肺部健康

• 批准号: 10633252
• 负责人: Umadevi Sivanappa Sajjan
• 金额: $ 45.13万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633252
• 关键词: Acceleration; Affect; Airway Disease; Anti-Inflammatory Agents; Antioxidants; Basal Cell; Basal Cell Hyperplasia; CDH1 gene; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cells; Chronic Obstructive Pulmonary Disease; Consumption; Cultured Cells; Data; Development; Diet; Epithelial Cells; Epithelium; Functional Regeneration; Genes; Goblet Cells; HOX protein; Health Benefit; Homeobox Genes; Homeostasis; Human; Immune response; Infection; Injury; Innate Immune Response; Knockout Mice; Lung; Lung diseases; Maintenance; Metaplasia; Molecular; Morphogenesis; Mus; Natural Immunity; Natural regeneration; Outcome; Pathologic; Pathway interactions; Patients; Placebos; Play; Property; Publishing; Pulmonary Inflammation; Quercetin; Regenerative pathway; Regulation; Repression; Research; Respiratory Tract Infections; Rhinovirus; Rhinovirus infection; Role; STC2 gene; Signal Transduction; Site; Squamous Cell; Testing; Tissues; adaptive immune response; adaptive immunity; airway epithelium; airway immune response; airway regeneration; airway remodeling; airway repair; bronchial epithelium; chemokine; cytokine; disease phenotype; epithelial repair; epithelium regeneration; improved; insight; knock-down; lung health; mouse model; non-smoker; novel; polarized cell; polyphenol; prevent; programs; pulmonary function; repaired; response; stem cells; transcriptional reprogramming; transcriptomics

PROJECT SUMMARY Patients with chronic obstructive pulmonary disease often show airway epithelial remodeling including basal cell hyperplasia, and goblet cell and squamous cell metaplasia. Such pathologic changes profoundly affect the outcome of respiratory infection as airway epithelium plays a crucial role in defining the innate and adaptive immunity in the lungs. Airway basal cells are the specialized stem cells and regenerate functional mucociliary- differentiated airway epithelium upon injury. The fact that COPD patients show airway epithelial remodeling indicate dysregulated repair mechanisms in airway basal cells. Our research suggests that quercetin, a natural polyphenol reverses airway epithelial remodeling in a mouse model of COPD. Our preliminary studies indicate that quercetin reprograms dysregulated repair pathways in COPD basal cells leading to regeneration of normal airway epithelium. We conducted transcriptomic analysis of airway basal cells from healthy non-smokers and COPD subjects and COPD basal cells treated with quercetin. Results from this microarray indicated dysregulation of genes involved in tissue development and epithelial differentiation in COPD cells. Intriguingly, the topmost differentially regulated genes in both these pathways are genes involved in lung morphogenesis HOXA1 and HOXB2. In normal basal cells, HOXA1 is highly expressed in basal cells, while HOXB2 expression increased at two weeks of culturing and correlated with polarization of cells, a prerequisite step in differentiation. COPD basal cells showed significantly reduced expression of both HOXA1 and HOXB2 and quercetin treatment increased expression of both genes. Based on these observations, we will examine a novel hypotheses that quercetin via modulation of HOXA1 and HOXB2 corrects the dysregulated repair mechanisms, thus improving immune responses to respiratory infections and lung function in COPD. In Specific Aim 1, we will determine the role of HOXA1 and HOXB2 in the regeneration of airway epithelium, and whether quercetin corrects the dysregulated repair mechanism in COPD by modulation of these HOX genes. In Specific Aim 2, we will examine the molecular mechanisms by which quercetin-induced HOXA1 and HOXB2 participates in the regeneration of airway epithelium. In Specific Aim 3, we will examine whether quercetin-induced HOXA1 and HOXB2 participate in limiting exaggerated innate immune responses to rhinovirus infection and prevent progression of lung disease in COPD. Finally, we will confirm whether quercetin treatment reduces airway epithelial remodeling in COPD patients and correlate with the expression of HOXA1 and HOXB2. Completion of these studies will provide important insight into airway epithelial regeneration and the mechanisms by which quercetin reduces airway epithelial remodeling in COPD.

项目摘要 慢性阻塞性肺疾病患者常表现为气道上皮重塑，包括基底细胞 增生、杯状细胞和鳞状细胞化生。这种病理变化深刻地影响着 呼吸道感染的结果，因为气道上皮在定义先天性和适应性 肺部的免疫力气道基底细胞是特化的干细胞，并再生功能性粘膜纤毛。 分化的气道上皮细胞。COPD患者气道上皮重塑 表明气道基底细胞的修复机制失调。我们的研究表明，槲皮素，一种天然的 多酚逆转COPD小鼠模型气道上皮重塑。我们的初步研究表明 槲皮素重新编程COPD基底细胞中失调的修复途径，导致正常细胞的再生， 气道上皮我们对健康非吸烟者的气道基底细胞进行了转录组学分析， COPD受试者和用槲皮素处理的COPD基底细胞。微阵列的结果表明 COPD细胞中参与组织发育和上皮分化的基因失调。有趣的是， 在这两条通路中最高的差异调节基因是与肺形态发生有关的基因 HOXA 1和HOXB 2。在正常的基底细胞中，HOXA 1在基底细胞中高表达，而HOXB 2在基底细胞中高表达。 在培养两周时增加，并与细胞极化相关，这是分化的先决条件。 COPD基底细胞显示HOXA 1和HOXB 2的表达和槲皮素处理显著降低， 这两种基因的表达都增加了。基于这些观察，我们将研究一个新的假设， 槲皮素通过调节HOXA 1和HOXB 2纠正失调的修复机制，从而改善 COPD患者对呼吸道感染的免疫应答和肺功能。在具体目标1中，我们将确定 HOXA 1和HOXB 2在气道上皮再生中的作用，以及槲皮素是否能纠正 通过调节这些HOX基因在COPD中的失调修复机制。在具体目标2中，我们将研究 槲皮素诱导的HOXA 1和HOXB 2参与再生的分子机制 气道上皮在具体目标3中，我们将研究槲皮素诱导的HOXA 1和HOXB 2是否参与了 在限制对鼻病毒感染的过度先天免疫应答和预防肺部疾病进展方面 慢性阻塞性肺病最后，我们将确认槲皮素治疗是否可以减少COPD的气道上皮重塑 与HOXA 1、HOXB 2表达相关。完成这些研究将提供 对气道上皮再生和槲皮素减少气道炎症的机制的重要见解 COPD中的上皮重塑。