Infection with gram-negative bacteria following multiple injury or burns is a common occurrence and often leads to a serious clinical syndrome known as multiorgan failure (MOF). Effective therapy in this patient group is lacking and consequently mortality rates are unacceptably high. It is our hypothesis that MOF results from the sustained production of mediators involved in host defense that initially are required to effectively combat infection, but with prolonged release contribute to injury of host cells. In many cases the development of MOF occurs after a period of weeks or even months so that the ability to block the initial events that temporally precede MOF might improve the outcome in these patients. The earliest responses to gram-negative infection are dependent upon recognition of endotoxin (LPS) by polymorphonuclear (PMN) leucocytes and monocytes/macrophages (MO). We now know that one pathway of LPS recognition by these cells involves complexes of LPS and a plasma protein, LPS binding protein (LBP) and a cell surface protein, CD14 that functions as a receptor for the LPS-LBP complex. Experiments are planned. to further define how the LBP/CD14 - dependent pathway influences LPS-dependent cell stimulation in basic studies using in vitro models that are relevant to events occurring in human disease. Findings derived from these basic studies will be used to develop investigations in animal models. Implicit in these studies is the development of new therapeutic strategies to intervene in clinical situations where gram-negative sepsis and endotoxemia are likely to occur.
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