Lipopolyamines: Novel antiendotoxin compounds that reduce mortality in experimental sepsis caused by gram-negative bacteria

The interactions of lipopolyamines, a class of structurally unique compound s currently being used as transfection (lipofection) agents, with lipopolys accharide (LPS) have been characterized. Our studies have demonstrated that 1,3-di-oleoyloxy-2-(6-carboxyspermyl) propylamide), available commercially as DOSPER, binds to purified LPS with an affinity of about 1/10 that of po lymyxin B. This essentially nontoxic compound inhibits, in a dose-dependent manner, LPS-induced activation of the Limulus clotting cascade and the pro duction of tumor necrosis factor alpha (TNF-alpha) interleukin-6 (IL-6), an d nitric oxide from LPS-stimulated J774.A1 cells, a murine macrophage-like cell line. Cytokine inhibition is paralleled by decreased steady-state leve ls of TNF-alpha and IL-6 mRNA and inhibits the nuclear translocation of nuc lear factor kappa B. These findings suggest that the lipopolyamine compound sequesters LPS, thereby blocking downstream cellular activation events tha t lead to the production of proinflammatory mediators. Administration of DO SPER to D-galactosamine-sensitized mice challenged either with LPS or with Escherichia coil organisms provided significant protection against lethalit y both with and without antibiotic chemotherapy. Partial protection is evid ent in LPS-challenged mice treated with DOSPER as late as 2 to 4 h followin g the endotoxin challenge, A greater degree of protection is observed in E. coli-challenged animals receiving ceftazidime than in those receiving imip enem, which is probably attributable to the higher levels of LPS released i n vivo by the former antibiotic. Potent antiendotoxic activity, low toxicit y, and ease of synthesis render the lipopolyamines candidate endotoxin-sequ estering agents of potential significant therapeutic value.