Hypothesis: combined inhibition of complement and CD14 as treatment regimen to attenuate the inflammatory response.

Pattern recognition is an essential event in innate immunity. Complement and Toll-like receptors (TLR), including the CD14 molecule, are two important upstream components of the innate immune system, recognizing exogenous structures as well as endogenous ligands. They act partly independent in the inflammatory network, but also have several cross-talk mechanisms which are under current investigation. Complement is an essential part of innate immunity protecting the host against infection. However, it is a double-edged sword since inappropriate activation may damage the host. Uncontrolled systemic activation of complement, as seen in severe sepsis, may contribute to the breakdown of homeostatic mechanisms leading to the irreversible state of septic shock. Complement inhibition is promising for protection of lethal experimental sepsis, but clinical studies are missing. Lipopolysaccharide (LPS) has been implicated in the pathogenesis of gram-negative sepsis by inducing synthesis of pro-inflammatory cytokines through binding to CD14 and the TLR4/MD-2 complex. Neutralization of LPS or blocking of CD14 has been effective in preventing LPS-induced lethal shock in animal studies, but results from clinical studies have been disappointing, as for most other therapeutic strategies. Based on some recently published data and further pilot data obtained in our laboratory, we hypothesize that inhibition of complement combined with neutralization of CD14 may attenuate the uncontrolled inflammatory reaction which leads to breakdown of homeostasis during sepsis. We further postulate this regimen as an approach for efficient inhibition of the initial innate recognition, exogenous as well as endogenous, to prevent downstream activation of the inflammatory reaction in general.