The long term objectives of the proposed research are to identify mechanisms of loss of human neutrophil chemotactic function which occurs in association with thermal injury and intra-abdominal infection and to identify treatments which will restore chemotactic function or prevent its loss.
Specific aims i n this application include: (1) supplementation of laboratory methods available to include the multiwell chamber membrane filter technique, to add three or chemoattractants to better consider the breadth of loss of patient neutrophil chemotactic function, and to develop methods to identify and physically isolate subpopulations of neutrophils; (2) continue our studies of patient neutrophil chemotactic dysfunction to verify our preliminary observation that the complement cascade is activated in plasma following thermal injury and during infection and that exposure of neutrophils to products of complement activation is in part responsible for loss of chemotactic migratory function; (3) continue our studies of control neutrophils to identify in vitro treatment conditions which alter both random and chemotactic migratory functions, to verify the role of oxygen metabolites in loss of random motility, and to model defects identified for patient neutrophil chemotactic function; and (4) to begin to consider in vitro conditions or treatments of patient neutrophils which restore chemotactic function. Host defense against infection involves several types of phagocytes and multiple cellular activities of these cells related to microbicidal function. Neutrophil chemotactic function is essential to the primary role of these cells in host defense against infection. There is much evidence to demonstrate that impaired motility alone may be sufficient to affect host defenses adversely. With the exception of several inherited disorders of neutrophil migratory function, mechanisms of loss of neutrophil chemotactic function in other situations remain poorly understood. We expect that information generated from experiments described in this application will add to our understanding of mechanisms of loss of neutrophil chemotactic function in thermal injury and infection. Information obtained will also have application to identification of treatments to prevent chemotactic dysfunction in these situations, to understanding monocyte and macraphage migratory functions, and to providing background for studies of complement activation in vivo and the role of products of complement activation in modulation of immune function in infection and cancer.
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