These experiments are designed to better understand the nature and consequences of neutrophil interaction with intestinal epithelia as often occurs in the active phase of inflammatory bowed disease. The long range philosophy of this project is to use reductionistic models of neutrophil- epithelial interactions in which mechanisms governing the interactions between these two cell types can be unraveled. Then, in the future, the mechanisms uncovered will be tested to see if similar specific interactions occur in nature. To accomplish this goal we use the human crypt epithelial model T84 since the crypt is the site at which neutrophil-epithelial interactions are most frequently noted in intestinal disease states. Purified human peripheral blood neutrophils will be used as the """"""""model"""""""" inflammatory cell. First, we will pursue findings that indicate that neutrophil-epithelial interactions elicit Cl secretion - the known basis of secretory diarrhea. Specifically, we will examine the regulation of a interactive purine metabolic pathway which appears to exist between intestinal epithelia and neutrophils. Second we will attempt to identify cytokine induced epithelial adhesive ligands for neutrophils which may be responsible for interferon-gamma-modulated neutrophil- epithelial cell interactions. Third, we will examine how direct contact between epithelial basolateral membranes and intraepithelial lymphocytes modulates epithelial function and subsequent neutrophil-epithelial interactions. Lastly, we will examine a natural signal (S. typhimurium) which appears to induce neutrophil transepithelial migration by mechanisms other than classically understood bacterial chemoattractants. Such data will provide insights into mechanisms of neutrophil-intestinal epithelial crosstalk during active inflammation and may thus provide new clues for strategic interference in these often deleterious intercellular interactions.
Showing the most recent 10 out of 42 publications
