Quercetin prevent airway epithelial remodeling and promote lung health in OPD

项目总结 慢性阻塞性肺疾病患者常表现为包括基底细胞在内的呼吸道上皮细胞重塑 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 呼吸道感染的转归作为呼吸道上皮细胞在确定先天和适应性中起着至关重要的作用 肺部的免疫力。呼吸道基底细胞是一种特化干细胞，可再生功能性粘液纤毛细胞。 损伤后分化的呼吸道上皮细胞。慢性阻塞性肺疾病患者呼吸道上皮细胞重塑的研究 提示呼吸道基底细胞的修复机制失调。我们的研究表明，作为一种天然的 多酚逆转慢性阻塞性肺疾病小鼠模型的呼吸道上皮重建。我们的初步研究表明 槲皮素重编程COPD基底层细胞异常修复通路导致正常 呼吸道上皮细胞。我们对健康的非吸烟者的呼吸道基底细胞进行了转录分析，并 慢性阻塞性肺疾病受试者和经栎素处理的慢性阻塞性肺疾病患者的基底细胞。这个微阵列的结果表明 COPD细胞中与组织发育和上皮分化相关的基因调控异常。有趣的是， 在这两条通路中，差异最大的基因是与肺形态发生有关的基因。 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。 慢性阻塞性肺疾病患者基底细胞HOXA1和HOXB2的表达均显著降低 两个基因的表达都增加了。基于这些观察，我们将检验一个新的假设，即 通过调节HOXA1和HOXB2，槲皮素纠正了失调的修复机制，从而改善了 慢性阻塞性肺疾病患者对呼吸道感染的免疫反应和肺功能。在具体目标1中，我们将确定 HOXA1和HOXB2在呼吸道上皮细胞再生中的作用 这些HOX基因调控COPD的失调修复机制。在具体目标2中，我们将研究 栎素诱导的HOXA1和HOXB2参与植物再生的分子机制 呼吸道上皮细胞。在特定的目标3中，我们将研究栎素诱导的HOXA1和HOXB2是否参与 限制对鼻病毒感染过度的先天免疫反应和防止肺部疾病的进展 在慢性阻塞性肺病。最后，我们将证实，在慢性阻塞性肺疾病中，槲皮素治疗是否能减少呼吸道上皮细胞重塑。 并与HOXA1和HOXB2的表达相关。这些研究的完成将提供 对呼吸道上皮再生和槲皮素减少呼吸道的机制的重要见解 慢性阻塞性肺疾病的上皮重塑。

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.