Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis

Subrina Jesmin; Satoshi Gando; Sohel Zaedi; Fumika Sakuraya

doi:10.1160/TH06-07-0379

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 96(06): 830-838
DOI: 10.1160/TH06-07-0379

Animal Models

Schattauer GmbH

Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis

Authors

Subrina Jesmin

¹Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Satoshi Gando

¹Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Sohel Zaedi

¹Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Fumika Sakuraya

¹Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Abstract

Summary

The liver can be injured and its functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the present study was to investigate the pattern of protease-activated receptors (PARs) over time in a model of acute liver injury induced by lipopolysaccharide (LPS); and whether PARs playa role in this process and exert their effects through inflammation and coagulation. Levels of tumor necrosis factor-α (TNF-α) were significantly expressed 1 h after LPS administration followed by: i) an increase in levels of tissue factor, factor VIIa, thrombin and plasminogen activator inhibitor-1; ii) unchanged or steady levels of tissue factor pathway inhibitor; and iii) subsequent deposition of fibrin in the liver tissue, that led to the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are associated with liver injury. The expression of all PAR isoforms (1–4) was elevated, and each isoform had a distinct cellular localization (hepatocytes, Kupffer cells, the portal triad area, and central veins) and a time-dependent pattern of expression. The immuno-reactivity of PAR2 and 4 in Kupffer cells was intense. Interestingly, PAR2 blocking peptide improved the healing of liver injuries, an effect that was associated with suppression of TNF-α elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. The present study reveals a distinct chronological expression and cellular localization of PARs in LPS-mediated liver injury and shows that blockade of PAR2 may playa crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.

Key words

Coagulation - endotoxin - inflammation - liver injury - protease-activated receptor (PAR)

Full Text

References

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