Title:A Novel Treatment Strategy for Sepsis and Septic Shock Based on the Interactions between Prostanoids, Nitric Oxide, and 20-Hydroxyeicosatetraenoic Acid
Volume: 11
Issue: 2
Author(s): Bahar Tunctan, Belma Korkmaz, Ayse Nihal Sari, Meltem Kacan, Demet Unsal, Mehmet Sami Serin, C. Kemal Buharalioglu, Seyhan Sahan-Firat, Wolf-Hagen Schunck, John R. Falck and Kafait U. Malik
Affiliation:
Keywords:
20-HETE, CYP4A, COX-2, iNOS, sepsis, septic shock
Abstract: Sepsis is a systemic inflammatory response syndrome with a suspected or proven infection caused by any
pathogen or a clinical syndrome associated with a high probability of infection. The definition of septic shock includes
sepsis-induced hypotension despite adequate fluid resuscitation, along with the presence of organ perfusion abnormalities,
and ultimately cell dysfunction. As the most common causes of morbidity and mortality in intensive care units worldwide,
the societal and economic costs of sepsis and septic shock are staggering. The molecular pathophysiology of sepsis and
septic shock and the complex roles played by cytokines, reactive oxygen and nitrogen species, and eicosanoids remain
controversal despite decades of study. The lipid A part of lipopolysaccharide, also known as endotoxin, is the most potent
microbial mediator of the pathogenesis of sepsis and septic shock. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a
vasoconstrictor ω-hydroxylation product of arachidonic acid that is produced by cytochrome P450 (CYP) enzymes,
mainly by CYP4A and CYP4F isoforms. Studies from our laboratory and others have provided substantial evidence that
administration of a synthetic analog of 20-HETE, N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine, prevents endotoxininduced
vascular hyporeactivity, hypotension, and mortality associated with increased formation of inducible nitric oxide
synthase-derived nitric oxide (NO) and cyclooxygenase-2-derived vasodilator prostanoids as well as decreased expression
and activity of CYP4A1 and 20-HETE production in a rodent model of septic shock. CYP4A- and CYP4F-derived 20-
HETE is also a proinflammatory mediator of endotoxin-induced acute systemic inflammation. In this review, we will present
an overview of our current understanding of the interactions between prostanoids, NO, and 20-HETE in sepsis, and
provide a rationale for the development of synthetic 20-HETE analogs for the treatment of sepsis and septic shock.
