Quercetin prevent airway epithelial remodeling and promote lung health in OPD

项目概要 慢性阻塞性肺疾病患者经常表现出气道上皮重塑，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方面起着至关重要的作用 肺部的免疫力。气道基底细胞是专门的干细胞，可再生功能性粘膜纤毛- 损伤后气道上皮发生分化。 COPD 患者表现出气道上皮重塑的事实 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是一种天然的 多酚可逆转 COPD 小鼠模型中的气道上皮重塑。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，从而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分析， 慢性阻塞性肺病受试者和用槲皮素治疗的慢性阻塞性肺病基底细胞。该微阵列的结果表明 参与慢性阻塞性肺病细胞组织发育和上皮分化的基因失调。有趣的是， 这两条途径中最重要的差异调节基因是参与肺形态发生的基因 HOXA1 和 HOXB2。在正常基底细胞中，HOXA1在基底细胞中高表达，而HOXB2在基底细胞中表达 培养两周时增加，并与细胞极化相关，这是分化的先决步骤。 COPD 基底细胞 HOXA1 和 HOXB2 的表达以及槲皮素治疗均显着降低 两个基因的表达增加。基于这些观察，我们将检验一个新的假设： 槲皮素通过调节 HOXA1 和 HOXB2 纠正失调的修复机制，从而改善 对呼吸道感染的免疫反应和慢性阻塞性肺病的肺功能。在具体目标 1 中，我们将确定 HOXA1和HOXB2在气道上皮再生中的作用，以及槲皮素是否可以纠正气道上皮再生 通过调节这些 HOX 基因来修复 COPD 失调的机制。在具体目标 2 中，我们将研究 槲皮素诱导HOXA1和HOXB2参与再生的分子机制 气道上皮。在具体目标 3 中，我们将检查槲皮素诱导的 HOXA1 和 HOXB2 是否参与 限制对鼻病毒感染的过度先天免疫反应并防止肺部疾病的进展 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慢性阻塞性肺病的气道上皮重塑 患者并与 HOXA1 和 HOXB2 的表达相关。完成这些研究将提供 对气道上皮再生和槲皮素减少气道的机制的重要见解 COPD 中的上皮重塑。

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.