Elsevier

Journal of Hepatology

Volume 32, Issue 1, January 2000, Pages 25-31
Journal of Hepatology

Enhanced monocyte activation and hepatotoxicity in response to endotoxin in portal hypertension

https://doi.org/10.1016/S0168-8278(00)80185-3Get rights and content

Abstract

Background/Aims: 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-α 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-α 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 μg/kg of lipopolysaccharide produced a 9-fold increase in plasma levels of tumor necrosis factor-α 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 μg/ml) induced a hypersecretion of tumor necrosis factor-α 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.

Section snippets

Animal preparation

Male Sprague-Dawley rats (weight 250–300 g) were obtained from Charles River, (Saint Aubin-lès-Elbeuf, France). Portal hypertension was induced as described (19) by partial portal vein ligation (PPVL) under ketamine anesthesia (Ketalar, 100 μg/kg body wt intramuscularly; Parke Davis, Inc., Morris Klein, NJ, USA). In brief, the portal vein was isolated and a calibrated constriction was performed using a single ligature of 3-0 silk around the portal vein and a 20-gauge blunt-tipped needle, which

Hemodynamics

Two weeks after ligation of the portal vein, PPVL rats had higher portal pressure (15.2±2.4 mmHg vs. 8.7±1.5 mmHg, p<0.05) and lower mean arterial pressure (104±4 mmHg vs.129±1 mmHg, p<0.05) than SHAM rats. Body weight at the time of the study was similar: 332±7 g in PPVL rats and 327±6 g in SHAM animals. The treatment with low doses of LPS (150 μg/kg ) had no significant effect on the mean arterial or portal pressure, and the significant differences between PPVL and SHAM animals were

Discussion

Septic shock is a multimediator disease. A large number of homeostatic systems may contribute directly or indirectly to the pathophysiology of septic shock, but no single mediator can explain all the features of this clinical entity. Moreover, there appears to be a complex interplay linking various systems to each other (3). Bacterial infections by Gram-negative organisms (including bacteremia, sepsis and spontaneous bacterial peritonitis) are usual complications in patients with cirrhosis and

Acknowledgements

We thank Dr. Deulofeu and Dr. Mas for technical assistance.

This study was supported by grants from the Comisión Interministerial de Ciencia y Tecnología (SAF 96-0120) (PB 94–1562) and Fundació Clínic per a la Recerca Biomèdica. SPP is a recipient of a grant from Formación del Personal Investigador (FP95 46731316).

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