Contribution of TNF-alpha to mucus cell production in asthma

描述(申请人提供)：哮喘是一种炎症性呼吸道疾病，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，继发于结构改变。这些呼吸道改变包括粘液细胞增殖/肥大，由于胶原和其他细胞外蛋白沉积而导致的气道基底膜厚度增加，血管增加，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)来阻止，但这是有争议的。肿瘤坏死因子-α是哮喘中一种重要的细胞因子，具有促炎症和促纤维化作用，在哮喘动物模型和人类中已发现其在促进呼吸道结构改变中的作用。重要的是，阻断肿瘤坏死因子-a效应的方法已被证明对其他一些慢性炎症性疾病相当有效。鉴于此背景，我的假设是，肿瘤坏死因子-α是哮喘中一种重要的细胞因子，在调节粘液细胞增殖方面发挥着重要作用。此外，使用抗肿瘤坏死因子-α抗体调节肿瘤坏死因子-α可能是治疗哮喘的一种合适的辅助疗法，可以预防或减轻粘液细胞的增生/肥大(小鼠系统中的化生)，并避免长期使用皮质类固醇的后果。这项建议的总体目标是评估肿瘤坏死因子-α在哮喘、粘液细胞增生/肥大的呼吸道病理的一个重要方面的作用。

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.