The relative role of complement and LPS in sepsis/SIRS: a rational for combined treatment with complement- and CD14/TLRs inhibitors.

The complement system is an essential part of innate immunity protecting the host against infection. However, it is a double-edged sward in the sense that inappropriate activation may damage host tissue. Uncontrolled systemic activation of complement, as seen in sepsis, may contribute to the breakdown of homeostatic mechanisms leading to the irreversible state of septic shock. Sepsis is a major health problem with high morbidity and the mortality is in the range of 30-70%. The pathopysiology is complex. T here are more than 200 putative mediators of sepsis and there have been more than 70 well designed clinical trials to test the effect of manipulation of a number of these mediators. The results in large have been disappointing. Endotoxin (LPS) has been im plicated in the pathogenesis of gram-negative sepsis by inducing synthesis of proinflammatory cytokines through binding to CD14 and the toll-like receptor 4 (TLR4)/MD-2 complex. Neutralisation of LPS or blocking of CD14 has been effective in preventing le thal shock in animal studies, but results from clinical studies have been disappointing as for most other therapeutic strategies. Based on pilot data recently obtained in vitro, we hypothesise that inhibition of complement using specific antibodies and pe ptides combined with neutralisation of LPS-induced effects by blocking CD14/TLRs may attenuate the uncontrolled inflammatory reaction which leads to breakdown of homeostasis during sepsis. This combined approach may be a therapeutic strategy in the treatm ent of sepsis. To test this hypothesis a number of candidate antibodies and peptides for complement inhibition and antibodies to block CD14/TLRs in pigs will be tested in vitro and the best candidates will be selected for the a combined therapeutic strate gy in a pig model of gram-negative sepsis.