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.