Molecular mechanisms of sepsis

In cancer, therapies are targeted at 6 important pathways. In sepsis, there is ongoing controversy regarding the number and relative roles of pathways that are activated or repressed and which are important in the progression from health to death. Adding to complexity, there is interaction of pathways, there are differences in temporal pattern of up and down-regulation of pathways and there are different responses of pathways to therapies of sepsis. In this review, we define four key pathways of sepsis: (1) inflammation and immunity, (2) coagulation and fibrinolysis, (3) apoptosis, and (4) endocrine. Each of these pathways can impair endothelial function, a unifying aspect of the pathophysiology of sepsis. There are few studies of interactions of pathways except for the interacttion of inflammation/immunity with coagulation/fibrinolysis. Successful treatment of cancer requires that cancer therapies interrupt several key pathways of cancer. Accordingly, we suggest that successful treatment of sepsis will require therapies that interrupt several key pathways of sepsis. Perhaps the paucity of approved therapies for sepsis is related in part to the underevaluation of novel pathways, to lack of understanding of interactions of pathways and to lack of interruption of key pathways of sepsis.