Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation

Naoaki Harada; Kenji Okajima; Mitsuhiro Uchiba; Hiroki Kurihara; Naomi Nakagata

doi:10.1160/TH05-09-0636

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(05): 788-795
DOI: 10.1160/TH05-09-0636

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation

Naoaki Harada

¹Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

,

Kenji Okajima

²Department of Biodefense Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

,

Mitsuhiro Uchiba

¹Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

,

Hiroki Kurihara

³Department of Physiological Chemistry and Metabolism, University of Tokyo Graduate School of Medicine, Tokyo, Japan

,

Naomi Nakagata

⁴Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan

› Author Affiliations

Abstract

Summary

We recently demonstrated that antithrombin (AT) reduces ischemia/reperfusion (I/R)-induced liver injury in rats by increasing hepatic tissue levels of calcitonin gene-related peptide (CGRP),a neuropeptide released from the sensory nerve endings. In the present study, we examined the effect of AT on I/Rinduced liver injury in wild type mice (CGRP^+/+) and congenitally αCGRP-deficient mice (CGRP^−/−). We also investigated any effects of AT on CGRP release from dorsal root ganglion neurons (DRG) isolated from CGRP^+/+. Based on results obtained in the present study, we attempted to determine if the anti-inflammatory activity of AT in vivo is dependent mainly on sensory neuron activation. AT enhanced ischemia/reperfusion-induced increases in hepatic tissue levels of CGRP and 6-keto-PGF_1α _, a stable metabolite of PGI₂, in CGRP^+/+, but it did not enhance these increases in CGRP^−/−. AT inhibited reperfusion-induced increases in serum alanine aminotransferase levels by increasing hepatic tissue blood flow and by attenuating increases in hepatic levels of tumor necrosis factor and myeloperoxidase in CGRP^+/+,although it showed neither of these therapeutic effects in CGRP^−/−. AT increased CGRP release from cultured DRGs only in the presence of anandamide, and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (PKA).AT markedly increased intracellular levels of cAMP in the presence of anandamide. These results strongly suggest that AT might reduce I/R-induced liver injury by enhancing activation of the sensory neurons through activation of PKA in sensory neurons.

Keywords

Antithrombin - capsaicin-sensitive sensory neurons - calcitonin gene-related peptide - liver injury - protein kinase A

Full Text

References

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