Current insights in sepsis: from pathogenesis to new treatment targets

Sepsis continues to be a leading cause of ICU death. This review summarizes current knowledge on sepsis pathogenesis and new therapeutical strategies.

Although systemic inflammatory response syndrome predominates in early sepsis, the compensatory anti-inflammatory response syndrome causes immunosuppression associated with late mortality. Toll-like receptors (TLR), the inflammasomes and other pattern-recognition receptors (PRR) initiate the host response after recognition of invading pathogens and endogenous danger signals. The TLR-regulated pro-inflammatory cytokines macrophage migration inhibitory factor and high-mobility-group-box-1 protein are promising treatment targets. Controversy on intensive insulin therapy, steroids, and activated protein C in sepsis has led to a re-evaluation of these immunomodulatory strategies. Interestingly, the anticoagulant protein C also exerts cytoprotective effects by neutralizing extracellular DNA. Endotoxin removal devices, TLR4-inhibitors, and restoration of sepsis-induced immunosuppression are other strategies being evaluated in sepsis patients.

Sepsis can be seen as a PRR-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. Detailed knowledge of host response pathways and new approaches in sepsis trial design, which take into account patient heterogeneity and the phase of the immunological response, represent major steps forward in sepsis research.