Molecular biology of endotoxin antagonism

The development of new therapies for the treatment of gram-negative bacterial sepsis has been the focus of extensive investigation. Molecular and cellular biologic techniques have led to important advances, including (1) identification of naturally occurring lipopolysaccharide (LPS)-binding proteins; (2) generation of novel LPS-binding antibodies, proteins, and peptides; and (3) characterization of the molecular determinants of LPS binding. In composite, these advances have facilitated comprehension of the manner in which gram-negative bacterial infection and concurrent endotoxemia exert detrimental effects on the mammalian host. The purpose of this review was to examine recent information regarding molecular determinants of LPS binding and the initial cellular signal transduction events, which lead to the local and systemic cytokine response and sepsis syndrome. Concurrently, the status of studies examining the effects of various endotoxin antagonists is reviewed. Data from these studies provide an indication of potential sites for therapeutic intervention as well as increasingly detailed understanding of the molecular mechanism of endotoxin antagonism. Taken together, these advances can be expected to further the development of the next generation of novel, adjuvant therapies for the treatment of sepsis syndrome caused by gram-negative bacterial infection and endotoxemia.