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New Paradigms in Sepsis: From Prevention to Protection of Failing Microcirculation.
J Thromb Haemost. 2015 Jul 18;
Authors: Hawiger J, Veach RA, Zienkiewicz J
Abstract
Sepsis, also known as septicemia, is one of the ten leading causes of death world-wide. 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 sepsis mechanism, resolution, and consequences for sepsis survivors are emerging. Consistent with Benjamin Franklin's dictum "an ounce of prevention is worth of 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 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, sepsis mortality approaches that of heart attacks and exceeds stroke deaths. More preventive vaccines and therapeutic measures are urgently needed. This article is protected by copyright. All rights reserved.
PMID: 26190521 [PubMed - as supplied by publisher]