Targeting Bacterial Endotoxin Two Sides of a Coin

摘要

The term sepsis describes a potentially lethal clinical condi tion that develops as a result of a dysregulated host response to bacterial infection. The most common bacterial component implicated in initiating the septic syndrome is a cell wall molecule derived from Gram-negative bacteria, known as lipopolysaccharide (LPS) or endotoxin. Like all mam mals, humans are equipped with an LPS-sensing machinery consisting, primarily, of LPS-binding protein (LBP), CD14, a glycosylphosphatidyl inositol (GPI)-anchored monocyte differentiation antigen, and toll-like receptor 4 (TLR4), a signal-transducing integral membrane protein. Modest stimulation of TLR4 facilitates the elimination of invading mi croorganisms. Potent TLR4 stimulation, however, produces severe reac tions in the host, often leading to multiple organ failure and death. The search for Pharmaceuticals that reduce mortality in septic patients has been a painstaking process. Thus far, only a few compounds have been found to significantly reduce mortality rates. Perhaps one of the more promising therapeutic strategies currently pursued is based on the iden tification of synthetic or naturally occurring substances that neutralize LPS or inhibit LPS-mediated activation of host immune cells, such as monocytes and macrophages. Here, we describe a number of diverse molecular structures with a capacity to either enhance or blunt LPS-induced monocyte activation. The underlying molecular mechanisms are discussed.