GOBLET CELL DYSFUNCTION IN ASTHMA

哮喘中的杯状细胞功能障碍

• 批准号: 2740145
• 负责人: John V Fahy
• 金额: $ 23.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-07 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2740145
• 关键词: allergens; asthma; bronchial mucus; cell morphology; cellular pathology; clinical research; corticosteroids; goblet cells; human subject; in situ hybridization; inhalation drug administration; messenger RNA; mucins; polymerase chain reaction; respiratory epithelium; secretion

The mechanisms of mucus hypersecretion in asthma are poorly understood, even though sputum production is a prominent symptom of asthma exacerbations, and mucus plugging of the airways is prominent in the airways of patients who die from acute severe asthma. Although goblet cell hyperplasia is a pathologic feature of animal models of asthma, and allergen-induced goblet cell degranulation causes airway obstruction in sensitized animals, the role of the goblet cell in the pathogenesis of mucus hypersecretion and airway obstruction in human asthma is not clear. We hypothesize that the phenotype of the airway epithelium in mild and moderate asthma is characterized by goblet cell hypertrophy and hyperplasia, placing these patients at risk for acute episodes of airway obstruction secondary to an exaggerated goblet cell degranulation response to stimuli such as allergen and viruses. We further hypothesize that overexpression of mucin genes in airway goblet cells is one mechanism for goblet cell hypertrophy and hyperplasia. We propose to test our hypotheses using rigorous methods of quantitative morphometry, in situ hybridization, and RT-PCR to quantify goblet cell size, goblet cell degranulation, and goblet cell expression of mucin genes in endobronchial biopsies obtained during bronchoscopy from healthy and asthmatic subjects. In addition, because the effects of current asthma treatments on goblet cells are unknown, and because there is a need for studies of specific treatments of goblet cell hyperplasia, we propose to begin to explore the treatment of goblet cell abnormalities in human asthma by examining the effects of inhaled corticosteroids on goblet cell hypersecretion, goblet cell mucin secretion, and goblet cell mucin gene expression. Aim 1 will determine if mRNA levels for MUC-2 and MUC-5AC are higher than normal in goblet cells in the airway epithelium of asthmatic subjects. Aim 2 will determine if goblet cell degranulation occurs in asthmatic subjects following allergen challenge. Aim 3 will determine if treatment with an inhaled corticosteroid decreases mucin stores in goblet cells, mucin secreted on the airway epithelial surface, and mucin mRNA levels in endobronchial biopsies. The proposed studies address an unmet need, because few studies have been published focusing on goblet cells in human asthma. The application of the methods described here provide the opportunity to begin to understand the relationship between goblet cell hypersecretion and airway obstruction in human asthma, and may suggest strategies for improving treatment.

哮喘中粘液分泌过多的机制知之甚少， 尽管痰的产生是哮喘的一个突出症状 急性加重，气道粘液堵塞在 死于急性严重哮喘的患者的气道。 虽然酒杯 细胞增生是哮喘动物模型的病理特征， 过敏原诱导的杯状细胞脱颗粒导致气道阻塞， 致敏动物，杯状细胞在发病机制中的作用， 粘液高分泌和气道阻塞在人类哮喘中不是 清楚 我们假设气道上皮细胞的表型在 轻度和中度哮喘的特征在于杯状细胞肥大， 增生，使这些患者处于急性呼吸道疾病发作的风险中。 继发于杯状细胞过度脱颗粒的阻塞 对过敏原和病毒等刺激的反应。 我们进一步 假设气道杯状细胞中粘蛋白基因过表达 是杯状细胞肥大和增生的一种机制。 我们 我建议用严格的定量方法来检验我们的假设。 形态测量、原位杂交和RT-PCR定量杯状细胞 粘蛋白大小、杯状细胞脱粒和杯状细胞表达 在支气管镜检查期间获得的支气管内活检中的基因， 健康和哮喘受试者。 此外，由于 目前对杯状细胞的哮喘治疗是未知的， 需要研究杯状细胞增生的特异性治疗， 我们建议开始探索杯状细胞的治疗 通过检查吸入的 糖皮质激素对杯状细胞高分泌，杯状细胞粘蛋白 分泌和杯状细胞粘蛋白基因表达。 目标1将决定 如果杯状组织中MUC-2和MUC-5AC的mRNA水平高于正常水平， 哮喘患者的气道上皮细胞。 目标2将 确定哮喘受试者是否发生杯状细胞脱颗粒 过敏原攻击后。 目标3将确定是否使用 吸入的皮质类固醇减少了杯状细胞中的粘蛋白储存， 分泌于气道上皮表面， 支气管内活检。 拟议的研究解决了一个未满足的需求， 因为很少有研究发表关注杯状细胞， 人类哮喘 本文所述方法的应用提供了 有机会开始了解杯状细胞与 高分泌和气道阻塞，并可能提示 改善治疗的策略。