This award is designed to test the hypothesis that trauma generates a serum suppressive factor responsible for decreased neutrophil bactericidal activity. This contributes to reduced host-resistance to infection after injury. This hypothesis will be tested in achieving the following specific aims:
Aim #1 is to determine the mechanism of action of this serum factor. The presence of a serum factor that suppresses neutrophil chemiluminescence has been detected following trauma. This factor is present in significant amounts only in the serum of patients who subsequently develop sepsis.
This aim i s to identify the cellular site of action of this suppressive factor by step-wise analysis of its effect on membrane binding, depolarization, NADPH oxidase, hexose monophosphate shunt activity, superoxide formation, and bacterial killing.
Aim #2 is to biochemically characterize this suppressor: a progressive protein purification scheme beginning with Sephadex G100 chromatography and ending with SDS-page will be used to biochemically characterize this suppressor. Following its isolation and purification, monospecific antiserum will be produced and confirmed using immunoelectrophoresis. This antisera will be used for quantitative measurement of this factor and to facilitate its removal in vitro.
Aim #3 will be to determine the role of this suppressor in contributing to decreased resistance to sepsis. A number of immunologic variables of presumed importance will be studied in multiple-trauma patients in an attempt to develop a predictive index of the subsequent risk for developing sepsis. These variables include the above mentioned serum neutrophil suppressor, lymphocyte suppression of a normal ongoing mixed lymphocyte reaction (MLR), opsonic fibronectin, and functional complement activity. Simultaneous analysis of these factors is important in order to avoid attributing development of sepsis to any one individual variable. A hierarchy of importance will be established using multiple regressions and a linear logistic model. The ultimate goal of this project is to contribute to the understanding of host immunobiology followig trauma, to establish with precision the biologic significance of a newly detected serum-suppressor of neutrophil bactericidal activity and to provide a rationale for future lines of investigation.
