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. ? ? ?
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