Pepducins — specially engineered lipidated peptides that act on the inside cell surface by blocking signalling from G-protein-coupled receptors (GPCRs) — have recently caused a stir in the pharmaceutical world when they showed promising results in the prevention of blood clotting and animal models of breast cancer. Now their engineers have turned to a further disease area — bacterial sepsis. Reporting in Nature Medicine, a team of scientists led by Athan Kuliopulos have developed this new class of compounds into a potential treatment for life-threatening systemic inflammatory response syndrome. These findings are of particular relevance, as, apart from fighting the underlying infection with antibiotics, the treatment of sepsis is currently largely limited to supportive strategies.
A crucial player in the pathogenesis of sepsis is the chemokine interleukin 8 (IL-8) — mice deficient for its receptor CXCR2 (a GPCR) are protected from developing sepsis. Kaneider et al. now report the development of pepducins based on the i3 and i1 intracellular loops of CXCR2 and CXCR1 (a second IL-8 receptor in humans) that proved to be extremely powerful in inhibiting IL-8 signalling: in human neutrophils, these compounds completely inhibited IL-8-induced calcium responses and migration towards IL-8 chemotactic gradients.
Using the caecal ligation and puncture (CLP) mouse model of lethal sepsis, the authors demonstrated that the survival rate of mice injected subcutaneously with these pepducins was dramatically enhanced: whereas 17/17 untreated mice died of sepsis, only one of 34 died in the group that received once-daily injections. Even when this treatment was delayed until 8 hours after the CLP procedure, the survival rate was still ∼86% (26/30), compared with 0% in the control group.
Further, the authors demonstrated that the blockade of CXCR1/CXCR2 signalling could reverse several criteria of an established systemic inflammatory response syndrome in mice. The levels of KC, the murine orthologue of IL-8, rapidly dropped after pepducin treatment; the numbers of neutrophils in bronchioalveolar lavage fluid was reduced; and pepducins conferred protection from lung and liver damage. Importantly, the pepducin treatment did not suppress leukocyte migration towards other chemokines, and so its effects can be considered immunomodulatory rather than immunosuppressive.
These results indicate that blockade of IL-8 signalling with pepducins reverses several criteria of established systemic inflammatory response syndrome in septic mice, and suggest that this approach could prove to be a powerful tool to combat sepsis, even in the setting of advanced disease.
ORIGINAL RESEARCH PAPER
Kaneider, N. C. et al. Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Nature Medicine 8 May 2005 (10/nm1245)
Kuliopulos, A. & Covic, L. Blocking receptors on the inside: pepducin-based intervention of PAR signalling and thrombosis. Life Sci. 74, 255–262 (2005)