The hepatic microvascular responses to sepsis

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. Mic robes and their virulence factors enter the hepatic circulation where they first activate sinusoidal endothelial cells and Kupffer cells to produce pr oinflammatory mediators, including TNF-alpha, IL-1, IL-6, reactive oxygen m etabolites, and eicosanoids. These mediators cause not only microbial killi ng, but also structural and functional liver damage concerning mainly the p arenchymal cells. Leukocytes are targeted to the liver sinusoids by chemoat tractants and, like platelets, tether to the sinusoidal endothelial cells, which are in a procoagulant state of inflammatory activation. Clogging of t he sinusoids by these cells leads to a decrease of blood flow through the s inusoids, which is further aggravated by endothelin-1 effectuating the cons triction of hepatic stellate cells in the sinusoids. In contrast, both nitr ic oxide (NO) and carbon monoxide (CO) act as antagonists of endothelin-1 b y mediating relaxation of sinusoidal vessels. By maintaining an adequate si nusoidal perfusion, both NO and CO are hepatoprotective during the early, h yperdynamic phase of sepsis characterized by an increased cardiac output an d moderate peripheral vasodilation. However, during the late, hypodynamic p hase of sepsis, massive overproduction of NO by the inducible NO synthase l eads to circulatory collapse, which inevitably includes breakdown of the li ver circulation.