The activation of human neutrophils under physiological conditions depends upon a balance of pathways which enhance or diminish the response of the cells to stimuli. We have been investigating the mechanisms of the pathways which modulate neutrophil responses to inflammatory stimuli. These include inhibitory hormones and priming agents such as LPS and its complexes. In studies completed during the first funding period we have shown that the LPS/LBP complex is a potent modulator of neutrophil function and that responses to LPS/LBP on neutrophils depend at least in part upon the expression of CD14. With respect to the inhibitory pathways, we have begun to characterize the kinetics and amplification of the catecholamine-dependent beta-adrenergic receptor system and begun to define intracellular targets for the inhibitory pathway. We have also developed methods to examine the regulation of cell function, to quantitate the expression of cell surface adhesive receptors and stimulatory receptors and the intracellular pathways which control the modulation in normal human blood donors. Novel flow cytometric technology has been developed to examine the behavior of cells in blood. These experimental systems reduce the concerns associated with how cells change during storage in blood or during isolation. We are now focusing our efforts on understanding the surface expression of CD14 on neutrophils and its possible role as a receptor for the LPS/LBP complex. Systematic new studies will characterize the interactions of the ligand with the receptor and the expression, function and processing of the receptor in control donors. In addition, we will examine the regulation of the receptor and its functions in trauma patients and the relevance of CD14 to the progress of ARDS and/or sepsis. We will evaluate the extent to which abnormal cell function arises from inhibition of cell responses as compared to """"""""exhaustion"""""""" of cell response capabilities.
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