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BACKGROUND & AIMS: Acute liver failure (ALF) is a rare clinical syndrome with high mortality resulting from hepatocellular necrosis and loss of function. In seronegative hepatitis (SNH), a T-cell-rich infiltrate leads to immune-mediated hepatocyte destruction, whereas in paracetamol poisoning, toxic metabolites induce hepatocyte necrosis, followed by a macrophage-rich, lymphocytic infiltrate that is an important factor in driving repair and regeneration. The nature of the hepatic inflammatory infiltrate, key to ALF pathogenesis and outcome, is determined by the recruitment of effector cells from blood, but the molecular basis of recruitment is poorly understood. To determine the phenotype of circulating and hepatic lymphocytes in patients with ALF secondary to paracetamol overdose (POD) or SNH and investigate the molecular basis of lymphocyte recruitment. METHODS: We used FACS, immunohistochemistry and flow-based adhesion assays to determine the regulation of lymphocyte adhesion. RESULTS: SNH and POD intrahepatic lymphocytes were αLβ2(hi) , CD69(hi) and CD38(hi) with a distinct homing phenotype being L-selectin(lo) , CXCR3(hi) and CCR5(+) . Expression of chemokine ligands for the receptors CCR5, CXCR3 and CXCR6 and the adhesion molecules ICAM-1, VCAM-1 and VAP-1 was markedly increased in the liver in ALF. Lymphocytes isolated from the livers of patients with SNH showed enhanced chemokine-dependent adhesion and transmigration across the human hepatic endothelium in vitro under flow and used a combination of β1 and β2 integrins to adhere to endothelium and β2 integrins, CD31 and VAP-1 to transmigrate. CONCLUSION: Aetiology-dependent combinations of adhesion molecules and chemokines expressed within tissue during ALF recruit lymphocytes with a distinct homing phenotype.
Bibliographical note© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
- acute liver failure
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- 2 Finished
Adams, D. & Wakelam, M.
15/01/04 → 31/03/07
Project: Research Councils