A Novel Treatment Strategy for Sepsis and Septic Shock Based on the Interactions between Prostanoids, Nitric Oxide, and 20-Hydroxyeicosatetraenoic Acid

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 endotox-ininduced 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.