Hepatic microvascular dysfunction and endotoxemia in sepsis
Authors: Tetsuji Fujita
Journal: Journal of Hepatology (2008)

I read with interest an excellent study aiming at elucidating the mechanisms of microcirculatory dysfunction in liver during sepsis by Dr. Singer and colleagues [[1]Singer G. Houghton J. Rivera C.A. Anthoni C. Granger D.N. Role of LPS in the hepatic microvascular dysfunction elicited by cecal ligation and puncture in mice.J Hepatol. 2007; 47: 799-806Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. In both endotoxin-sensitive and insensitive mice, cecal ligation and puncture (CLP) resulted in the accumulation of leukocytes and platelets in terminal hepatic venules, blood cell recruitment in sinusoids, and increased nonperfused sinusoids. CLP elicited also increases in the expression of myeloid differentiation factor 88 and Toll-like receptor 2, both of which have an important role in the signaling of endotoxin and other toxins. These findings caused by CLP were similar to those in mice subjected to a moderate dose of endotoxin. At the end of this experiment, endotoxin was not detected in CLP mice, whereas mean endotoxin levels were 653.7 Endotoxin Unit (EU)/ml in the portal blood and 561.4 EU/ml in inferior vena cava following intraperitoneal injection of endotoxin at a dose of 500 μg/kg. Based on the above findings, the authors conclude that endotoxin does not play a critical role in the hepatic microvascular disturbances in mice after CLP, which is a model of polymicrobial sepsis in human. Microcirculatory dysfunction lies at the center of sepsis pathogenesis. This study may shed light on the underlying mechanisms of sepsis-induced microvascular dysfunction leading to hepatic failure. I would like to raise some issues concerning the endotoxin concentrations. Although 1 EU was initially defined as the endotoxin activity of 200 pg of a Reference Standard Endotoxin, the conversion ratio is dependent on the source of the endotoxin. There is a considerable variation of the equation, ranging from 1 EU to 20 pg to 1 EU to 500 pg. I would like to ask the authors whether endotoxin concentrations should be expressed as pg/ml rather than EU/ml because the authors determined the doses of endotoxin injected to the mice to be 50 or 500 μg/kg. The absence of endotoxin in the blood does not necessarily indicate that endotoxin is not involved in the hepatic microvascular dysfunction in mice subjected to CLP. Prompt clearance of endotoxin has been observed. For example, in a human model of acute endotoxemia evoked by a bolus injection of 2 ng/kg of endotoxin, endotoxin is rapidly cleared from the circulation within 30 min [[2]van Deventer S.J.H. Büller H.R. ten Cate J.W. Aarden L.A. Hack C.E. Stuck A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways.Blood. 1990; 12: 2620-2626Google Scholar]. Rapid binding of endotoxin to the target cell has also been identified. In vitro, endotoxin is able to bind the cell surface within 1 min of exposure, and only 5–15 min exposure is sufficient to trigger maximal TNF-α release [[3]Gallay P. Jongeneel C.V. Barras C. Burnier M. Baumgartner J.D. Galuser M.P. et al.Short time exposure to lipopolysaccharide is sufficient to activate human monocytes.J Immunol. 1993; 150: 5086-5093PubMed Google Scholar].