Diseases of the airway such as chronic bronchitis, asthma, and cystic fibrosis have a prominent inflammatory component and chief among the inflammatory cells in the airway is the neutrophil (PMN). Though it is well-known that PMNs can cause tissue damage under some circumstances, (for example, the alveolus), it is not so clear that this is the case for the airway. Recent experiments have failed to connect PMN infiltration of airways produced by airway instillation of LTB4 in man with any biologic consequence. Although PMN infiltration has been associated with the development of airway reactivity in several models, the two phenomena have been dissociated without noticeable attenuation of the airway reactivity. On the other hand, PMNs and PMN elastase have been associated with considerable damage in lungs and airways. PMN elastase is capable of producing emphysema and mucous metaplasia in the airways of animals and the mucous differentiation of the airways in response to pollutants such as cigarette smoke is attenuated by antiinflammatory agents. In airways, PMN elastase cleaves important protective proteins such as immunoglobulins and complement components and alters the surface receptors on epithelial cells and on PMNs themselves. A systematic examination of the interaction of PMNs and airway epithelial cells has not been undertaken. Therefore we will test the hypotheses that: (1) in the absence of prior epithelial damage, PMNs are not cytotoxic for HTE cells; (2) prior damage of HTE cells by virus infection or pollutant exposure alters the interaction of the cells with PMNs such that cytotoxicity is now manifest. (3) PMN elastase alters the barrier function of the epithelium, receptor functions on the cell surface, mucous secretion, ion transport, and eicosanoid production in HTE cells. We will use HTE cells in culture for these studies, both primary cultures and cell lines developed by James Jacobberger at our institution which retain many of the differentiated functions of epithelia. Using cells in culture will permit us to isolate the PMN-epithelial cell interactions from the influence of the other cell types in the airways and to understand them better.
Showing the most recent 10 out of 152 publications
