Contribution of TNF-alpha to mucus cell production in asthma

TNF-α 对哮喘粘液细胞产生的贡献

• 批准号: 7143457
• 负责人: PAULA J BUSSE
• 金额: $ 11.33万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143457
• 关键词: asthma; hyperplasia; hypertrophy; mucus; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Asthma is an inflammatory airways disease which is often characterized by reversible obstruction. In certain patients, however, this inflammation may lead to irreversible obstruction, secondary to structural changes. These airway changes include mucus cell hyperplasia/hypertrophy, increased thickness of the airway basement membrane by deposition of collagen and other extracellular proteins, increased vascularity, altered neuronal responses and hypertrophy of the airway smooth muscle. Current evidence suggests that these changes may not be prevented with anti-inflammatory treatment such as corticosteroids, but this is controversial. TNF-a is an important cytokine in asthma which has both proinflammatory and profibrotic properties and its role in promoting structural changes in the airway has been noted in animal models of asthma and in humans. Importantly, approaches to block the effects of TNF-a have proven to be quite effective in a number of other chronic inflammatory diseases. Given this background, it is my hypothesis that TNF-a is an important cytokine in asthma in the regulation of mucus-cell hyperplasia. Furthermore, modulation of TNF-a, using an anti-TNF-a antibody may be an appropriate adjunctive therapy in asthma, preventing or attenuating mucus-cell hyperplasia/hypertrophy (metaplasia in the murine system) and avoiding the consequences of long-term corticosteroid use. The overall goal of this proposal is to evaluate the effects of TNF-a on an important aspect of airway pathology in asthma, mucus-cell hyperplasia/hypertrophy.

描述（由申请人提供）：哮喘是一种炎症性气道疾病，其特征通常是可逆性阻塞。然而，在某些患者中，这种炎症可能会导致不可逆的阻塞，继发于结构变化。这些气道变化包括粘液细胞增生/肥大、胶原蛋白和其他细胞外蛋白沉积导致的气道基底膜厚度增加、血管分布增加、神经元反应改变和气道平滑肌肥大。目前的证据表明，皮质类固醇等抗炎治疗可能无法预防这些变化，但这是有争议的。 TNF-a 是哮喘中的一种重要细胞因子，具有促炎和促纤维化特性，并且在哮喘动物模型和人类中已注意到其在促进气道结构变化中的作用。重要的是，阻断 TNF-a 作用的方法已被证明对许多其他慢性炎症性疾病非常有效。鉴于此背景，我假设 TNF-a 是哮喘中调节粘液细胞增生的重要细胞因子。此外，使用抗 TNF-a 抗体调节 TNF-a 可能是哮喘的适当辅助治疗，可预防或减轻粘液细胞增生/肥大（小鼠系统中的化生）并避免长期皮质类固醇的后果使用。该提案的总体目标是评估 TNF-a 对哮喘气道病理学重要方面、粘液细胞增生/肥大的影响。