Protective role of phospholipid oxidation products in endotoxin-induced tissue damage

Valery N. Bochkov, Alexandra Kadl, Joakim Huber, Florian Gruber, Bernd R. Binder and Norbert Leitinger ()
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Valery N. Bochkov: University of Vienna
Alexandra Kadl: University of Vienna
Joakim Huber: University of Vienna
Florian Gruber: University of Vienna
Bernd R. Binder: University of Vienna
Norbert Leitinger: University of Vienna

Nature, 2002, vol. 419, issue 6902, 77-81

Abstract: Abstract Lipopolysaccharide (LPS), an outer-membrane component of Gram-negative bacteria, interacts with LPS-binding protein and CD14, which present LPS to toll-like receptor 4 (refs 1, 2), which activates inflammatory gene expression through nuclear factor κB (NFκB) and mitogen-activated protein-kinase signalling3,4. Antibacterial defence involves activation of neutrophils that generate reactive oxygen species capable of killing bacteria5; therefore host lipid peroxidation occurs, initiated by enzymes such as NADPH oxidase and myeloperoxidase6. Oxidized phospholipids are pro-inflammatory agonists promoting chronic inflammation in atherosclerosis7; however, recent data suggest that they can inhibit expression of inflammatory adhesion molecules8. Here we show that oxidized phospholipids inhibit LPS-induced but not tumour-necrosis factor-α-induced or interleukin-1β-induced NFκB-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock. Thus, in severe Gram-negative bacterial infection, endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Furthermore, identified chemical structures capable of inhibiting the effects of endotoxins such as LPS could be used for the development of new drugs for treatment of sepsis.

Date: 2002
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DOI: 10.1038/nature01023

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