Original communicationAttenuation of proinflammatory gene expression and microcirculatory disturbances by endothelinA receptor blockade after orthotopic liver transplantation in pigs
Section snippets
Material and methods
The investigation was performed in accordance with the German legislation on protection of animals, and the experiments were approved by the Committee on Animal Care (Regierungspräsidium Leipzig, Germany; No. 02/00). Orthotopic liver transplantation was performed in female German Landrace pigs (20-25 kg). The control group (n = 10) received 50 mL of isotonic saline solution, and the therapy group (n = 10) received intravenously 5 mg/kg of body weight of the specific ETA-RA BSF 208075 (Knoll AG,
Survival
Pigs surviving to postoperative day 7 were killed. The number of survivors at postoperative 7 was 7 of 10 in the control group and 9 of 10 in the therapy group. In the control and therapy group, 1 of 10 pigs, respectively, died within the first 2 days because of cardiopulmonary complications. In the control group, 2 of 10 pigs died because of liver failure.
Macrohemodynamic and blood gas changes
Before operation, there were no differences in mean arterial blood pressure between the control and therapy groups under isoflurane
Discussion
In hepatic I/R, dysfunction of the microcirculation appears to be the primary process that triggers the final manifestation of tissue injury. Postischemic microcirculatory dysfunction includes failure of sinusoidal perfusion (ie, the no-reflow), which is caused by endothelial swelling, intravascular hemoconcentration, and a dysbalance between the vasoactive mediators endothelin and nitric oxide. Apart from perfusion failure, I/R further promotes a microcirculation-associated inflammatory
Conclusion
Our results indicate that ETA-receptor antagonism has beneficial effects on the outcome after cold I/R injury of the porcine liver by improving microcirculation and decreasing histologic damages. Furthermore, findings from the present study suggest that selective antagonism of the ETA receptor also may have anti-inflammatory potential through suppression of the mRNA expression of the genes of proinflammatory cytokines such as TNFα, IL-1β, and IL-6. This study was designed as a pilot project to
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Supported by a grant from the Else Kröner-Fresenius Stiftung, a junior research fund of the Medical Faculty at the University of Leipzig, and a grant from Fujisawa, Germany.