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  • Open Access

Antithrombin reduces ischemia/reperfusion-induced liver injury in mice by enhancing the activation of sensory neurons through protein kinase A activation

  • 1,
  • 1,
  • 2 and
  • 3
Critical Care200610 (Suppl 1) :P159

https://doi.org/10.1186/cc4506

  • Published:

Keywords

  • Dorsal Root Ganglion
  • Liver Injury
  • Sensory Neuron
  • Dorsal Root Ganglion Neuron
  • Antithrombin

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/R-induced liver injury in wildtype mice (CGRP+/+) and congenital α CGRP-deficient mice (CGRP-/-). We further investigated whether AT affects CGRP release from dorsal root ganglion neurons (DRG) isolated from CGRP+/+. Based on results obtained in the present study, we attempted to determine whether the anti-inflammatory activity of AT in vivo is dependent mainly on sensory neuron activation. AT enhanced I/R-induced increases in hepatic tissue levels of CGRP and 6-keto-PGF a stable metabolite of PGI2, in CGRP+/+, while 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+/+, while it showed neither of these therapeutic effects in CGRP-/-. AT increased CGRP release from cultured DRGs only in the presence of anandamide, and the AT-induced increase in CGRP release was not observed in the presence of KT5720, an inhibitor of protein kinase A (PKA). AT markedly increased intracellular levels of cAMP in the presence of anandamide. In conclusion, 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.

Authors’ Affiliations

(1)
Department of Biodefense Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
(2)
Department of Physiological Chemistry and Metabolism, University of Tokyo Graduate School of Medicine, Tokyo, Japan
(3)
Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan

Copyright

© BioMed Central Ltd 2006

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