Inflammation of both the upper and lower airways is a common event in man resulting clinically in sinusitis, bronchitis and asthma. Diseases of the airways account for a serious morbidity problem around the world and significant mortality is associated with complications from these diseases. Although inflammatory infiltrates of granulocytic and/or monocytic cells characterize most acute and chronic airway diseases, factors leading to establishment and maintenance of inflammation are poorly understood. The pathologic consequences of cellular infiltration are represented by a spectrum of effects from being entirely reversible to causing permanent tissue injury. In certain diseases, the cellular infiltration is cell specific. For example, allergic inflammation leads to eosinophil infiltration and the resulting pathologic process becomes defined by a specificity for eosinophil recruitment. Although the reasons for an eosinophil-specific sequestration response are not yet understood, and the chemotactic factors responsible are not identified, the phenomena is well documented in a number of both upper and lower airway disorders. Infiltration of activated eosinophils to local tissue sites results in numerous complex cell-cell interactions that promote the inflammatory condition. It is our hypothesis that whenever the eosinophil is prominently involved, prolonged cell-cell interactions of major significance occur between infiltrating eosinophils and the resident epithelial cells within the inflamed airway. Therefore, we conclude that under the influence of soluble factors derived from the epithelial cells, the eosinophils arc recruited, become activated and exhibit prolonged survival. Furthermore, we conclude that the epithelial cells, in turn, are upregulated by the infiltrating eosinophils and participate in promoting and/or regulating the inflammatory response. Ultimately, cytokines, complement, and acute phase proteins generated by these airway epithelial cells may play a significant role in the disease processes. This proposal will focus on the molecular and cellular interactions between eosinophils and epithelial cells in the airway. Specifically, we will identity l) eosinophil-derived mediators which alter the regulatory responses of epithelial cells; 2) epithelial-derived mediators responsible for activation and survival of eosinophils; and 3) epithelial cell and monocyte-derived mediators which modulate the inflammatory process. Our goal is to understand the mechanisms underlying the predominance of eosinophils in inflamed airways and their contribution to the disease state.
|Jagels, M A; Daffern, P J; Hugli, T E (2000) C3a and C5a enhance granulocyte adhesion to endothelial and epithelial cell monolayers: epithelial and endothelial priming is required for C3a-induced eosinophil adhesion. Immunopharmacology 46:209-22|
|Jagels, M A; Daffern, P J; Zuraw, B L et al. (1999) Mechanisms and regulation of polymorphonuclear leukocyte and eosinophil adherence to human airway epithelial cells. Am J Respir Cell Mol Biol 21:418-27|
|Daffern, P J; Jagels, M A; Saad, J J et al. (1999) Upper airway epithelial cells support eosinophil survival in vitro through production of GM-CSF and prostaglandin E2: regulation by glucocorticoids and TNF-alpha. Allergy Asthma Proc 20:243-53|
|Daffern, P J; Muilenburg, D; Hugli, T E et al. (1999) Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses. J Allergy Clin Immunol 104:559-64|