Enhanced monocyte activation and hepatotoxicity in response to endotoxin in portal hypertension.
OBJECTIVE
Septic shock is a systemic response to infection, and it causes a high mortality rate in cirrhotic patients. The mechanisms responsible for this susceptibility in cirrhosis are poorly understood. The aim of this study was to investigate whether monocyte activation and hepatic function are altered in portal hypertension after endotoxin administration.


METHODS
Portal-hypertensive and sham-operated rats were used. Plasma levels of tumor necrosis factor-alpha after lipopolysaccharide stimulation (both in vivo and in vitro) were measured by ELISA. CD11b/CD18 integrin expression on leukocyte membrane was measured by flow cytometry. Plasma transaminase activities were also determined.


RESULTS
The levels of tumor necrosis factor-alpha in plasma and the expression of CD11b/CD18 on leukocytes in portal-hypertensive rats was similar to that in sham-operated rats. Injection of 150 microg/kg of lipopolysaccharide produced a 9-fold increase in plasma levels of tumor necrosis factor-alpha in portal-hypertensive compared with sham-operated rats, together with a significant up-regulation of CD11b/CD18 expression on monocytes and an elevation in plasma transaminase activity. Blood leukocytes incubated in vitro with lipopolysaccharide (0.5 microg/ml) induced a hypersecretion of tumor necrosis factor-alpha in portal-hypertensive rats, as compared to sham-operated rats.


CONCLUSIONS
This study shows that monocytes from portal-hypertensive rats have an enhanced response to endotoxin, leading to hepatotoxicity.
Pérez del Pulgar
S
S
Hepatic Hemodynamic Laboratory, Liver Unit, IDIBAPS, Hospital Clinic, Barcelona, Spain.
Pizcueta
P
P
Engel
P
P
Bosch
J
J
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D018821:CD18 Antigens / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000209:etiology; D004926:Escherichia coli; D006975:Hypertension, Portal / Q000097:blood*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018821:CD18 Antigens; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase