Lipopolyamines

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

Sunil A. David, Richard Silverstein, Claudia R. Amura, Tammy L Kielian, David C. Morrison

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

The interactions of lipopolyamines, a class of structurally unique compounds currently being used as transfection (lipofection) agents, with lipopolysaccharide (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 polymyxin B. This essentially nontoxic compound inhibits, in a dose-dependent manner, LPS-induced activation of the Limulus clotting cascade and the production of tumor necrosis factor alpha (TNF-α) interleukin-6 (IL-6), and nitric oxide from LPS-stimulated J774.A1 cells, a murine macrophage-like cell line. Cytokine inhibition is paralleled by decreased steady-state levels of TNF-α and IL-6 mRNA and inhibits the nuclear translocation of nuclear factor kappa B. These findings suggest that the lipopolyamine compound sequesters LPS, thereby blocking downstream cellular activation events that lead to the production of proinflammatory mediators. Administration of DOSPER to D-galactosamine-sensitized mice challenged either with LPS or with Escherichia coli organisms provided significant protection against lethality both with and without antibiotic chemotherapy. Partial protection is evident in LPS-challenged mice treated with DOSPER as late as 2 to 4 h following the endotoxin challenge. A greater degree of protection is observed in E. coli-challenged animals receiving ceftazidime than in those receiving imipenem, which is probably attributable to the higher levels of LPS released in vivo by the former antibiotic. Potent antiendotoxic activity, low toxicity, and ease of synthesis render the lipopolyamines candidate endotoxin-sequestering agents of potential significant therapeutic value.

Original languageEnglish (US)
Pages (from-to)912-919
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume43
Issue number4
StatePublished - Apr 1 1999

Fingerprint

Gram-Negative Bacteria
Lipopolysaccharides
Sepsis
Mortality
Endotoxins
Interleukin-6
Sequestering Agents
Tumor Necrosis Factor-alpha
Escherichia coli
Anti-Bacterial Agents
Horseshoe Crabs
Galactosamine
Ceftazidime
Imipenem
NF-kappa B
Transfection
Nitric Oxide
Macrophages
Cytokines
Drug Therapy

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Lipopolyamines : Novel antiendotoxin compounds that reduce mortality in experimental sepsis caused by gram-negative bacteria. / David, Sunil A.; Silverstein, Richard; Amura, Claudia R.; Kielian, Tammy L; Morrison, David C.

In: Antimicrobial Agents and Chemotherapy, Vol. 43, No. 4, 01.04.1999, p. 912-919.

Research output: Contribution to journalArticle

David, Sunil A. ; Silverstein, Richard ; Amura, Claudia R. ; Kielian, Tammy L ; Morrison, David C. / Lipopolyamines : Novel antiendotoxin compounds that reduce mortality in experimental sepsis caused by gram-negative bacteria. In: Antimicrobial Agents and Chemotherapy. 1999 ; Vol. 43, No. 4. pp. 912-919.
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