Contribution of TNF-alpha to mucus cell production in asthma

描述（由申请人提供）：哮喘是一种炎症性气道疾病，通常以可逆性阻塞为特征。然而，在某些患者中，这种炎症可能导致不可逆的梗阻，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，这些变化可能无法通过抗炎治疗如皮质类固醇来预防，但这是有争议的。TNF-α是哮喘中的重要细胞因子，其具有促炎和促纤维化特性，并且其在促进气道结构变化中的作用已经在哮喘的动物模型和人类中被注意到。重要的是，阻断TNF-α作用的方法已被证明在许多其他慢性炎性疾病中非常有效。在此背景下，我假设TNF-α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可能是哮喘中适当的连续疗法，预防或减弱粘液细胞增生/肥大（鼠系统中的化生）并避免长期使用皮质类固醇的后果。本提案的总体目标是评价TNF-α对哮喘气道病理学的重要方面，即粘液细胞增生/肥大的影响。

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.