ABSTRACT
The liver is believed to play a major role in the initiation of multiorgan failure,
the most lethal complication in the clinical course of sepsis. Microbes and their
virulence factors enter the hepatic circulation where they first activate sinusoidal
endothelial cells and Kupffer cells to produce proinflammatory mediators, including
TNF-α, IL-1, IL-6, reactive oxygen metabolites, and eicosanoids. These mediators cause
not only microbial killing, but also structural and functional liver damage concerning
mainly the parenchymal cells. Leukocytes are targeted to the liver sinusoids by chemoattractants
and, like platelets, tether to the sinusoidal endothelial cells, which are in a procoagulant
state of inflammatory activation. Clogging of the sinusoids by these cells leads to
a decrease of blood flow through the sinusoids, which is further aggravated by endothelin-1
effectuating the constriction of hepatic stellate cells in the sinusoids. In contrast,
both nitric oxide (NO) and carbon monoxide (CO) act as antagonists of endothelin-1
by mediating relaxation of sinusoidal vessels. By maintaining an adequate sinusoidal
perfusion, both NO and CO are hepatoprotective during the early, hyperdynamic phase
of sepsis characterized by an increased cardiac output and moderate peripheral vasodilation.
However, during the late, hypodynamic phase of sepsis, massive overproduction of NO
by the inducible NO synthase leads to circulatory collapse, which inevitably includes
breakdown of the liver circulation.
KEYWORD
Liver - sepsis - microcirculation - sinusoids - endothelial cells
