Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation.
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 wild type mice (CGRP(+/+)) and congenitally alphaCGRP-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(1alpha), a stable metabolite of PGI(2), 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.[1]References
- Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation. Harada, N., Okajima, K., Uchiba, M., Kurihara, H., Nakagata, N. Thromb. Haemost. (2006) [Pubmed]
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