GOBLET CELL DYSFUNCTION IN ASTHMA

哮喘中的杯状细胞功能障碍

• 批准号: 6476884
• 负责人: John V Fahy
• 金额: $ 21.61万
• 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 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476884
• 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尚不清楚，

项目成果

"Reactive airways disease". A lazy term of uncertain meaning that should be abandoned.

“反应性气道疾病”。

• DOI: 10.1164/ajrccm.163.4.2005049
• 发表时间: 2001
• 期刊: American journal of respiratory and critical care medicine.
• 作者: Fahy,JV;O'Byrne,PM
• 通讯作者: O'Byrne,PM

Asthma: prevalence, pathogenesis, and prospects for novel therapies.

哮喘：患病率、发病机制和新疗法的前景。

• DOI: 10.1001/jama.286.4.395
• 发表时间: 2001
• 期刊: JAMA
• 作者: Woodruff,PG;Fahy,JV
• 通讯作者: Fahy,JV

Epithelial desquamation in asthma: artifact or pathology?

哮喘中的上皮脱落：人为因素还是病理原因？

• DOI: 10.1164/ajrccm.162.6.2001041
• 发表时间: 2000
• 期刊: American journal of respiratory and critical care medicine.
• 作者: Ordonez,C;Ferrando,R;Hyde,DM;Wong,HH;Fahy,JV
• 通讯作者: Fahy,JV

Allergen challenge causes inflammation but not goblet cell degranulation in asthmatic subjects.

过敏原激发会导致哮喘受试者炎症，但不会导致杯状细胞脱颗粒。

• DOI: 10.1067/mai.2001.119162
• 发表时间: 2001
• 期刊: The Journal of allergy and clinical immunology.
• 作者: Hays,SR;Woodruff,PG;Khashayar,R;Ferrando,RE;Liu,J;Fung,P;Zhao,CQ;Wong,HH;Fahy,JV
• 通讯作者: Fahy,JV