Thrombin and Protease-Activated Receptor-1 Agonists Promote Lipopolysaccharide-Induced Hepatocellular Injury in Perfused Livers
Open Access
- 24 January 2003
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 305 (2), 417-425
- https://doi.org/10.1124/jpet.102.046391
Abstract
Bacterial lipopolysaccharide (LPS) is a potent inflammatory agent capable of producing liver injury, the pathogenesis of which depends on numerous mediators, including thrombin. Previous studies showed that thrombin promotes LPS-induced liver injury independent of its ability to form fibrin clots. In isolated, buffer-perfused livers from LPS-treated rats, thrombin added to the perfusion buffer caused dose-dependent liver injury with an EC50 value of 0.4 nM, consistent with activation by thrombin of a protease-activated receptor (PAR). Actions of thrombin at PARs can be mimicked by thrombin receptor-activating peptides (TRAPs). TRAPs for PAR-1 reproduced the injury caused by thrombin in isolated livers, suggesting that one mechanism by which thrombin promotes LPS-induced liver injury is by activating PAR-1. Immunocytochemistry demonstrated the presence of PAR-1 on sinusoidal endothelial cells and Kupffer cells but not on parenchymal cells or neutrophils. Previous studies showed that thrombin interacts with neutrophils in the genesis of liver injury after LPS treatment. To explore this interaction further, the influence of thrombin on mediators that modulate neutrophil function were evaluated. Inhibition of thrombin in LPS-treated rats prevented liver injury but did not prevent up-regulation of cytokine-induced neutrophil chemoattractant-1, macrophage inflammatory protein-2, or intercellular adhesion molecule-1. Thrombin inhibition did, however, prevent neutrophil (PMN) degranulation in vivo as measured by plasma elastase levels. In addition, elastase concentration was increased in the perfusion medium of livers isolated from LPS-treated rats and perfused with TRAPs. These results suggest that activation of PAR-1 after LPS exposure promotes PMN activation and hepatic parenchymal cell injury.Keywords
This publication has 30 references indexed in Scilit:
- Neutrophil Elastase Inhibitor Attenuates Lipopolysaccharide-Induced Hepatic Microvascular Dysfunction in MiceShock, 2002
- Protease-activated receptors: sentries for inflammation?Trends in Pharmacological Sciences, 2000
- Effects of Pre-existing Rhinitis on Ozone-Induced Mucous Cell Metaplasia in Rat Nasal EpitheliumToxicology and Applied Pharmacology, 1999
- Proteinase-activated receptors: structural requirements for activity, receptor cross-reactivity, and receptor selectivity of receptor-activating peptidesCanadian Journal of Physiology and Pharmacology, 1997
- Ligand Cross-reactivity within the Protease-activated Receptor FamilyPublished by Elsevier BV ,1996
- Identification of factors from rat neutrophils responsible for cytotoxicity to isolated hepatocytesJournal of Leukocyte Biology, 1996
- Blockade of liver macrophages by gadolinium chloride reduces lethality in endotoxemic rats—analysis of mechanisms of lethality in endotoxemiaJournal of Leukocyte Biology, 1994
- Relationship between tumor necrosis factor-alpha and neutrophils in endotoxin-induced liver injuryAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 1993
- Cellular effects of thrombin: pharmacology of the receptor(s) in various cell types and possible development of receptor antagonistsPharmacological Research, 1993
- Essential groups in synthetic agonist peptides for activation of the platelet thrombin receptorBiochemistry, 1992