JPET Assistant Professor of Medicine (Clinician-Educator)

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 24, 2003; DOI: 10.1124/jpet.102.046391

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.102.046391v1
305/2/417    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Copple, B. L.
Right arrow Articles by Roth, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Copple, B. L.
Right arrow Articles by Roth, R. A.

Vol. 305, Issue 2, 417-425, May 2003

Thrombin and Protease-Activated Receptor-1 Agonists Promote Lipopolysaccharide-Induced Hepatocellular Injury in Perfused Livers

Bryan L. Copple, Frederic Moulin, Umesh M. Hanumegowda, Patricia E. Ganey and Robert A. Roth

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

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.

0022-3565/03/3052-0417$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
J. P. Luyendyk, G. H. Cantor, D. Kirchhofer, N. Mackman, B. L. Copple, and R. Wang
Tissue factor-dependent coagulation contributes to {alpha}-naphthylisothiocyanate-induced cholestatic liver injury in mice
Am J Physiol Gastrointest Liver Physiol, April 1, 2009; 296(4): G840 - G849.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
N. Nitescu, E. Grimberg, S.-E. Ricksten, N. Marcussen, H. Nordlinder, and G. Guron
Effects of thrombin inhibition with melagatran on renal hemodynamics and function and liver integrity during early endotoxemia
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2007; 292(3): R1117 - R1124.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. P. Luyendyk, L. D. Lehman-McKeeman, D. M. Nelson, V. M. Bhaskaran, T. P. Reilly, B. D. Car, G. H. Cantor, X. Deng, J. F. Maddox, P. E. Ganey, et al.
Coagulation-Dependent Gene Expression and Liver Injury in Rats Given Lipopolysaccharide with Ranitidine but Not with Famotidine
J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 635 - 643.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
N. D. Kim, J.-O. Moon, A. L. Slitt, and B. L. Copple
Early Growth Response Factor-1 Is Critical for Cholestatic Liver Injury
Toxicol. Sci., April 1, 2006; 90(2): 586 - 595.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. P. Luyendyk, P. J. Shaw, C. D. Green, J. F. Maddox, P. E. Ganey, and R. A. Roth
Coagulation-Mediated Hypoxia and Neutrophil-Dependent Hepatic Injury in Rats Given Lipopolysaccharide and Ranitidine
J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1023 - 1031.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
B. L. Copple, C. M. Rondelli, J. F. Maddox, N. C. Hoglen, P. E. Ganey, and R. A. Roth
Modes of Cell Death in Rat Liver after Monocrotaline Exposure
Toxicol. Sci., January 1, 2004; 77(1): 172 - 182.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
T. Minami, A. Sugiyama, S.-Q. Wu, R. Abid, T. Kodama, and W. C. Aird
Thrombin and Phenotypic Modulation of the Endothelium
Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 41 - 53.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
S. B. Yee, J. R. Harkema, P. E. Ganey, and R. A. Roth
The Coagulation System Contributes to Synergistic Liver Injury from Exposure to Monocrotaline and Bacterial Lipopolysaccharide
Toxicol. Sci., August 1, 2003; 74(2): 457 - 469.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
S. B. Yee, U. M. Hanumegowda, B. L. Copple, M. Shibuya, P. E. Ganey, and R. A. Roth
Endothelial Cell Injury and Coagulation System Activation during Synergistic Hepatotoxicity from Monocrotaline and Bacterial Lipopolysaccharide Coexposure
Toxicol. Sci., July 1, 2003; 74(1): 203 - 214.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2003 by the American Society for Pharmacology and Experimental Therapeutics.