Lipopolysaccharide: An Endotoxin or an Exogenous Hormone?

Conventional models of the pathogenesis of sepsis assume that microorganisms or their products are necessarily injurious to the host. In contrast, an evolutionary perspective suggests that host-microbial interactions are a symbiotic model and that disease results from the disruption of a mutually beneficial homeostatic state. Lipopolysaccharide (LPS) from gram-negative bacteria is a prototypical trigger of sepsis and a target for the development of novel therapeutics. The biological mechanisms underlying the recognition of, and response to, LPS are more characteristic of a hormone than of a toxin. All mammals carry endogenous stores of LPS and express dedicated carrier proteins, a cellular receptor complex, and mechanisms that specifically antagonize the response to LPS. Disruption of any component of this complex recognition system jeopardizes host defenses against infection with exogenous microorganisms. Thus, LPS is not less an endotoxin than an exohormone, and its neutralization may potentially result in either benefit or harm.