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

N Harada,K Okajima,N Nakagata,H Kuhihara

doi:10.1186/cc4506

Abstract

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-PGF1α 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.

Highlights

Tight blood glucose (BG) control has been shown to videos of the alveolar dynamics
Computer-advised insulin infusion in postoperative cardiac surgery patients: a randomized prospective controlled multicenter trial quality the alveoli are observed at an open chest wall under a glass plate representing an artificial situation. To circumvent this restriction we developed a method of intravital endoscopy and tested it on an animal rat model
J Cordingley1, J Plank2, J Blaha3, M Wilinska4, L Chassin4, Methods In cooperation with Schoelly GmbH (Denzlingen, C Morgan1, S Squire1, M Haluzik3, J Kremen3, S Svacina3, Germany) we developed an endoscope with an outer tube diameter

Summary

Introduction

Tight blood glucose (BG) control has been shown to videos of the alveolar dynamics. The thorax remains intact.decrease morbidity and mortality in critically ill patients [1] but is Results Figure 1 shows a tissue area after lavage of 0.8 mm difficult to achieve using standard insulin infusion protocols. Results Patient characteristics (mean ± SD): age 57.4 ± 15.4 years, 28 female, 52 male, APACHE II score 28.2 ± 6.6; number of organ failures 4.0 ± 1.12; preceding ICU period 8.5 ± 9.3 days; continuous sedation with midazolam 31.2 ± 34.2 mg/hour, fentanyl 0.12 ± 0.08 mg/hour, propofol 45.6 ± 105.2 mg/hour; sedation assessment according to RS 5.65 ± 0.63, CPS 5.15 ± 1.67, CKS 0.65 ± 0.69, CS 9.34 ± 2.13 und LSS 1.78 ± 1.69, RASS –4.50 ± 1.27, FiO2 0.52 ± 0.17, PEEP 8.2 ± 2.4 cmH2O, ventilatory frequency 20.5 ± 4.8/min, pressure control 16.8 ± 4.4 cmH2O, tidal volume 540 ± 115 ml, TVV 2525.6 ± 11,366 ml (minimum 1.52; maximum 91,586). We hypothesized that S100β levels correlate with this tumor’s preoperative characteristics and with perioperative neurological injury despite its supratentorial location and non-neural origin

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