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

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.

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Figure 1: OxPAPC selectively inhibits LPS-induced intracellular signalling and expression of inflammatory adhesion molecules in HUVEC.
Figure 2: OxPAPC inhibits effects of LPS by blocking interactions of LPS with LBP and CD14.
Figure 4: The anti-endotoxin activity of OxPAPC is not mimicked by other lipids, crucially depends on OxPAPC oxidation, and is not mediated by free radicals.
Figure 3: Oxidized phospholipids inhibit effects of endotoxin in vivo.

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Acknowledgements

This project was funded by the Austrian Science Foundation and by the ICP Program of the Austrian Federal Ministry for Education, Science and Culture.

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Correspondence to Norbert Leitinger.

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Bochkov, V., Kadl, A., Huber, J. et al. Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. Nature 419, 77–81 (2002). https://doi.org/10.1038/nature01023

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