Sepsis, also known as
septicemia, is one of the 10 leading causes of death worldwide. The rising tide of
sepsis due to bacterial, fungal and
viral infections cannot be stemmed by current antimicrobial
therapies and supportive measures. New paradigms for the mechanism and resolution of
sepsis and consequences for
sepsis survivors are emerging. Consistent with Benjamin Franklin's dictum 'an ounce of prevention is worth a pound of cure',
sepsis can be prevented by vaccinations against pneumococci and meningococci. Recently, the NIH NHLBI Panel redefined
sepsis as 'severe endothelial dysfunction syndrome in response to intravascular and extravascular
infections causing reversible or irreversible injury to the microcirculation responsible for
multiple organ failure'. Microvascular endothelial injury underlies
sepsis-associated
hypotension,
edema,
disseminated intravascular coagulation,
acute respiratory distress syndrome and
acute kidney injury. Microbial genome products trigger 'genome wars' in
sepsis that reprogram the human genome and culminate in a 'genomic storm' in blood and vascular cells.
Sepsis can be averted experimentally by endothelial cytoprotection through targeting nuclear signaling that mediates
inflammation and deranged metabolism. Endothelial 'rheostats' (e.g. inhibitors of NF-κB, A20
protein, CRADD/RAIDD
protein and
microRNAs) regulate endothelial signaling. Physiologic 'extinguishers' (e.g. suppressor of
cytokine signaling 3) can be replenished through intracellular
protein therapy.
Lipid mediators (e.g.
resolvin D1) hasten
sepsis resolution. As
sepsis cases rose from 387 330 in 1996 to 1.1 million in 2011, and are estimated to reach 2 million by 2020 in the US, mortality due to
sepsis approaches that of
heart attacks and exceeds deaths from
stroke. More preventive
vaccines and therapeutic measures are urgently needed.