CELLULAR AND MOLECULAR MECHANISMS OF AIRWAY INFLAMMATION

点击翻译按钮获取中文摘要

This application is to continue multidisciplinary studies of normal airway cells and to elucidate cellular and molecular mechanisms associated with airway inflammation. Drs. Nadel, Basbaum, Caughey, and McDonald have collaborated closely in this PPG for many years, and they will use their diverse skills to study airway inflammatory processes using cell biological, molecular, morphologic and physiologic approaches. The investigators will examine effects in surface epithelial, endothelial, gland, and inflammatory cells and their interactions that are involved in inflammatory responses, factors that influence the quality and magnitude of these responses, consequences of acute inflammation, and novel strategies for reducing airway inflammation. One component of the Program Project will define cellular mechanisms by which plasma leakage occurs at sites of inflammation, with the goal of bridging the gap between in vitro studies of the mechanisms of endothelial leakage and in vivo measurements of the effects of inflammatory mediators on vascular permeability. Because no single mechanism is likely to explain all types of vascular leakage in the respiratory tract, model systems of acute inflammation (neurogenic inflammation) and more prolonged inflammation (late phase allergic response) will be compared. Factors that can increase or decrease the response of endothelial cells to inflammatory mediators will also be studied. A second component will address the contribution of airway epithelium to inflammation. Because the airway epithelium exists at the interface with the external environment, it is ideally positioned to signal irritants that are inhaled, such cigarette smoke, pollutants, viruses and bacteria; these cells are strategically located to respond to inhaled irritants. Neutrophil products are implicated in inflammatory responses, and airway epithelial cells (among others) produce a cytokine, interleukin-8 (IL-8) that is a potent chemoattractant. The purpose is to elucidate the roles of IL-8 in inflammatory responses to foreign irritants. The cells responsible for IL_8 and factors that modify these responses will be explored. Tools for studying IL-8 in humans and dogs are being developed. Studies of human tissues will include permanent human airway epithelial cell lines, lung tissues and cells from transplant donors and recipients. Dog airways will be studied in vivo and in vitro, using molecular tools developed in this laboratory. A third component of the Program Project will examine molecular mechanisms responsible for gland hypertrophy. Mechanisms controlling proliferation, migration, and differentiation of gland cells will be explored with a focus on growth factors and growth factor receptors that participate in gland growth. The action of locally produced proteases in the degradation and penetration of the extracellular matrix by growing mucosal glands will also be defined. The fourth component examines the contributions of mast cell proteases to airway tissue responses. Chemical, histological, and physiological approaches will be utilized to explore the roles of mast cell serine and metalloproteases in airway inflammation. In particular, the studies will examine the participation of mast cell proteases in inflammatory airway tissue growth and remodeling. Furthermore, the interactions of the proteases with blood vessels and the role of the proteases in modulating vascular permeability will be examined. Finally, the structure, cellular expression and functions of a newly discovered mast cell protease, dMCP-3 will be determined. This Program Project team has a long tradition of collaborative research and the use of multidisciplinary strategies for studying airway inflammation. The aim is to make it possible to develop more effective strategies for preventing or reducing the plasma extravasation, mucosal thickening, mucus production, and airflow obstruction associated with asthma, bronchitis, cystic fibrosis and other inflammatory airway diseases.