Role of Squamous Metaplasia in Small Airways Disease in COPD

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DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) is caused by loss of the walls of air sacs and by narrowing of the airways due to scarring. Currently, there are no effective therapies to treat COPD. While the loss of alveoli is unlikely to be reversible, the narrowing of the airways represents a possible therapeutic target. TGF-¿ is a potent molecule that causes scarring and there is ample evidence that it plays a role in airway wall narrowing. However, TGF-¿ must be made active before it can function. Our preliminary data suggest that in COPD, TGF-¿ activation is caused by two other molecules, called integrins, located on the surface of airway cell types. Furthermore, our pilot studies suggest that integrin-mediated TGF-¿ activation in airway cell types correlates with worsening airway obstruction. This data suggests that integrins might be novel therapeutic targets in COPD. Major toxic components of tobacco smoke are oxygen free radicals. Free radicals likely play a role in amplifying integrin expression and integrin-mediated TGF-¿ activation since our preliminary data suggest that reactive oxygen species (ROS) initiate a self-amplifying loop of integrin-mediated activation of TGF-¿. Ultimately, increased TGF-¿ activation leads to replacement of the ciliated airway lining cells with squamous epithelium (called squamous metaplasia), which resemble epidermal cells. Furthermore, our recently published studies suggest that the squamous epithelium that has replaced the normal ciliated epithelium of the airway begins to elaborate the other proteins that stimulate scarring of the airways. Squamous metaplasia is associated with airway obstruction in COPD but has traditionally been viewed as an adaptive response to environmental stress rather than a part of the pathogenic process. Our studies are the first, to our knowledge, that suggest that squamous metaplasia may actively contribute to the pathogenesis of airway thickening. Here, in this proposal, we test the hypothesis that integrins contribute to squamous metaplasia, which increases integrin-dependent activation of TGF-¿ by the cells of the airway wall, which leads to airway wall thickening. We will use freshly derived primary human airway cell types for these investigations to maximize the application of our findings to human disease. The successful completion of this project will be a crucial translation step in establishing the role and mechanism of squamous metaplasia in small airways disease in COPD. PUBLIC HEALTH RELEVANCE: The experiments proposed, utilizing primary human cell systems are the first to explore the role and mechanism of squamous metaplasia in the pathogenesis of airway wall thickening in COPD. Successful completion of this proposal will provide a much needed advance in the field as it will explore the mechanisms of cigarette-smoke induced squamous metaplasia and the elaboration of fibrogenic cytokines by the squamous metaplasia cells. These will be key experiments that will identify av¿6 and squamous metaplasia as therapeutic agents in COPD.