SUPPRESSION OF MURINE ENDOTOXIN RESPONSE BY E5531, A NOVEL SYNTHETIC LIPID-A ANTAGONIST

As a consequence of blood-borne bacterial sepsis, endotoxin or lipopol ysaccharide (LPS) from the cell walls of gram-negative bacteria can tr igger an acute inflammatory response, leading to a series of pathologi cal events and often resulting in death. To block this inflammatory re sponse to endotoxin, a novel lipid A analogue, E5531, was designed and synthesized as an LPS antagonist, and its biological properties were examined in vitro and in vivo. In murine peritoneal macrophages, E5531 inhibited the release of tumor necrosis factor alpha (TPF-alpha) by E scherichia call LPS with a 50% inhibitory concentration (IC50) of 2.2 nM, while E5531 elicited no significant increases in TNF-alpha on its own. In support of a mechanism consistent with antagonism of binding t o a cell surface receptor for LPS, E5531 inhibited equilibrium binding of radioiodinated LPS 2-(r-azidosalicylamido)-1,3'-dithiopropionate-L PS) to mouse macrophages with an IC50 of 0.50 mu M. E5531 inhibited LP S-induced increases in TNF-alpha in vivo when it was coinjected with L PS into C57BL/6 mice primed with Mycobacterium bovis bacillus Calmette -Guerin (BCG). In this model, the efficacy of E5531 was inversely corr elated to the LPS challenge dose, consistent with a competitive antago nist-like mechanism of action. Blockade of the inflammatory response b y E5531 could further be demonstrated in other in vivo models: E5531 p rotected BCG-primed mice from LPS-induced lethality in a dose-dependen t manner and suppressed LPS-induced hepatic injury in Propionibacteriu m acnes-primed or galactosamine-sensitized mice. These results argue t hat the novel synthetic lipid A analogue E5531 can antagonize the acti on of LPS in in vitro and suppress the pathological effects of LPS in vivo in mice.