Pathophysiology, staging and therapy of severe sepsis in baboon models

•  Introduction•  Modeling the shock/disseminated intravascular coagulation (DIC) variant of severe sepsis using the LD 100 baboon model of E. coli sepsis  ‐ Principles arising from the studies carried out in the LD 100 E. coli model•  Studies of severe sepsis‐induced organ failure using the LD 50 baboon model of E. coli sepsis  ‐ Ischemia‐reperfusion and oxidative stress as drivers of the second stage  ‐ Therapeutic targets during the second stage of sepsis    ‐ Complement activation    ‐ Circulating histones•  Lessons learned from the baboon models of sepsisWe review our baboon models of Escherichia coli sepsis that mimic, respectively, the shock/disseminated intravascular coagulation (DIC) and organ failure variants of severe sepsis, and analyse the pathophysiologic processes that are unique to each. The multi‐stage, multi‐factorial characteristics of severe sepsis develop as a result of the initial insult, which – depending on its intensity – activates components of the intravascular compartment leading to overwhelming shock/DIC; or initiates a sequence of events involving both the intra‐ and extravascular (tissues) compartments that lead to organ failure. In the latter case, the disorder passes through two stages: an initial inflammatory/coagulopathic intravascular first stage triggered by E. coli , followed by an extravascular second stage, involving components unique to each organ and triggered by ischemia/reperfusion (oxidative stress and histone release). Although a myriad of overlapping cellular and molecular components are involved, it is the context in which these components are brought into play that determine whether shock/DIC or organ failure predominate. For example, inflammatory and thrombotic responses amplified by thrombin in the first case whereas similar responses are amplified by complement activation products in the second. Rather than blocking specific mediators, we found that attenuation of the thrombin and complement amplification pathways can effectively reverse the shock/DIC and organ failure exhibited by the LD 100 and LD 50 E. coli models of severe sepsis, respectively. Translation of these concepts to successful intervention in the respective baboon models of E. coli sepsis and the application to their clinical counterparts is described.