title: Current insights in sepsis: from pathogenesis to new treatment targets.
abstract: OBJECTIVE
  Sepsis continues to be a leading cause of ICU death. This review summarizes current knowledge on sepsis pathogenesis and new therapeutical strategies.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Center for Molecular Medicine and Division of Infectious Diseases, Academic Medical Centre, Amsterdam, the Netherlands. w.j.wiersinga@amc.uva.nl
authors: W Joost
authors: WJ
authors: Wiersinga
mesh_terms: D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D051192:Receptors, Pattern Recognition / Q000502:physiology; D018805:Sepsis / Q000175:diagnosis / Q000209:etiology* / Q000628:therapy*
chemical_list: D018836:Inflammation Mediators; D051192:Receptors, Pattern Recognition