Journal
NATURE MEDICINE
Volume 11, Issue 6, Pages 661-665Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1245
Keywords
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Funding
- NHLBI NIH HHS [R01 HL 64701] Funding Source: Medline
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We describe a new therapeutic approach for the treatment of lethal sepsis using cell-penetrating lipopeptides - termed pepducins - that target either individual or multiple chemokine receptors. Interleukin-8 (IL-8), a ligand for the CXCR1 and CXCR2 receptors, is the most potent endogenous proinflammatory chemokine in sepsis. IL-8 levels rise in blood and lung fluids to activate neutrophils and other cells, and correlate with shock, lung injury and high mortality(1-5). We show that pepducins derived from either the i1 or i3 intracellular loops of CXCR1 and CXCR2 prevent the IL-8 response of both receptors and reverse the lethal sequelae of sepsis, including disseminated intravascular coagulation and multi-organ failure in mice. Conversely, pepducins selective for CXCR4 cause a massive leukocytosis that does not affect survival. CXCR1 and CXCR2 pepducins conferred nearly 100% survival even when treatment was postponed, suggesting that our approach might be beneficial in the setting of advanced disease.
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