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Inhibition of TXA synthesis with OKY-046 improves liver preservation by prolonged hypothermic machine perfusion in rats.
J Gastroenterol Hepatol 2008; 23(7 Pt 2):e212-20JG

Abstract

BACKGROUND AND AIM

We previously reported that hypothermic machine perfusion (HMP) for liver preservation is feasible, but hepatic microcirculatory dysfunction and significant liver damage remain major obstacles in its application when the preservation is extended to 24 h. The underlying injury mechanism is not well understood. The present study sought to investigate the role of thromboxane A(2) (TXA(2)) in the pathogenesis of liver injury after prolonged HMP.

METHODS

Livers isolated from Sprague-Dawley rats were subjected to continuous machine perfusion with University of Wisconsin (UW) solution at a flow rate of 0.4 mL/min/g liver at 4 degrees C for 24 h. A specific TXA(2) synthase inhibitor, OKY-046 (OKY), was added to UW solution during the preservation period and to the Krebs-Henseleit buffer during reperfusion. The performance of the livers after preservation was evaluated using an isolated liver perfusion system with Krebs-Henseleit buffer at a flow rate of 15 mL/min at 37 degrees C for 30 min.

RESULTS

Prolonged HMP induced a significant release of TXA(2) into the portal circulation as indicated by markedly increased levels of TXB(2) in the perfusate during reperfusion (at 30 min, 1447.4 +/- 163.6 pg/mL vs 50.91 +/- 6.7 pg/mL for control). Inhibition of TXA(2) synthesis with OKY significantly decreased releases of TXA(2) (69.8 +/- 13.4 pg/mL) concomitant with reduced lactate dehydrogenase (LDH) releases (at 30 min, HMP + OKY: 144.9 +/- 27.9 U/L; HMP: 369.3 +/- 68.5 U/L; simple cold storage or SCS: 884.4 +/- 80.3 U/L), decreased liver wet/dry weight ratio (HMP + OKY vs SCS and HMP: 3.6 +/- 0.3 vs 4.4 +/- 0.1 and 3.9 +/- 0.2, respectively) and increased hyaluronic acid uptake (at 30 min, HMP + OKY vs SCS, HMP: 33.1 +/- 2.9% vs 13.9 +/- 3.6%, 18.6 +/- 2.4%, respectively). Liver histology also showed significant improvement in tissue edema and hepatocellular necrosis with OKY compared with HMP without OKY.

CONCLUSION

The results demonstrate that TXA(2) is involved in the development of hepatocellular injury induced by HMP, and inhibition of TXA(2) synthesis during preservation and reperfusion protects liver hepatocytes and sinusoidal endothelial cells from injuries caused by prolonged HMP.

Authors+Show Affiliations

Department of Biology, University of North Carolia at Charlotte, Charlotte, North Carolina 28223, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17645480

Citation

Xu, Hongzhi, et al. "Inhibition of TXA Synthesis With OKY-046 Improves Liver Preservation By Prolonged Hypothermic Machine Perfusion in Rats." Journal of Gastroenterology and Hepatology, vol. 23, no. 7 Pt 2, 2008, pp. e212-20.
Xu H, Lee CY, Clemens MG, et al. Inhibition of TXA synthesis with OKY-046 improves liver preservation by prolonged hypothermic machine perfusion in rats. J Gastroenterol Hepatol. 2008;23(7 Pt 2):e212-20.
Xu, H., Lee, C. Y., Clemens, M. G., & Zhang, J. X. (2008). Inhibition of TXA synthesis with OKY-046 improves liver preservation by prolonged hypothermic machine perfusion in rats. Journal of Gastroenterology and Hepatology, 23(7 Pt 2), pp. e212-20.
Xu H, et al. Inhibition of TXA Synthesis With OKY-046 Improves Liver Preservation By Prolonged Hypothermic Machine Perfusion in Rats. J Gastroenterol Hepatol. 2008;23(7 Pt 2):e212-20. PubMed PMID: 17645480.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of TXA synthesis with OKY-046 improves liver preservation by prolonged hypothermic machine perfusion in rats. AU - Xu,Hongzhi, AU - Lee,Charles Y, AU - Clemens,Mark G, AU - Zhang,Jian X, Y1 - 2007/07/20/ PY - 2007/7/25/pubmed PY - 2008/10/31/medline PY - 2007/7/25/entrez SP - e212 EP - 20 JF - Journal of gastroenterology and hepatology JO - J. Gastroenterol. Hepatol. VL - 23 IS - 7 Pt 2 N2 - BACKGROUND AND AIM: We previously reported that hypothermic machine perfusion (HMP) for liver preservation is feasible, but hepatic microcirculatory dysfunction and significant liver damage remain major obstacles in its application when the preservation is extended to 24 h. The underlying injury mechanism is not well understood. The present study sought to investigate the role of thromboxane A(2) (TXA(2)) in the pathogenesis of liver injury after prolonged HMP. METHODS: Livers isolated from Sprague-Dawley rats were subjected to continuous machine perfusion with University of Wisconsin (UW) solution at a flow rate of 0.4 mL/min/g liver at 4 degrees C for 24 h. A specific TXA(2) synthase inhibitor, OKY-046 (OKY), was added to UW solution during the preservation period and to the Krebs-Henseleit buffer during reperfusion. The performance of the livers after preservation was evaluated using an isolated liver perfusion system with Krebs-Henseleit buffer at a flow rate of 15 mL/min at 37 degrees C for 30 min. RESULTS: Prolonged HMP induced a significant release of TXA(2) into the portal circulation as indicated by markedly increased levels of TXB(2) in the perfusate during reperfusion (at 30 min, 1447.4 +/- 163.6 pg/mL vs 50.91 +/- 6.7 pg/mL for control). Inhibition of TXA(2) synthesis with OKY significantly decreased releases of TXA(2) (69.8 +/- 13.4 pg/mL) concomitant with reduced lactate dehydrogenase (LDH) releases (at 30 min, HMP + OKY: 144.9 +/- 27.9 U/L; HMP: 369.3 +/- 68.5 U/L; simple cold storage or SCS: 884.4 +/- 80.3 U/L), decreased liver wet/dry weight ratio (HMP + OKY vs SCS and HMP: 3.6 +/- 0.3 vs 4.4 +/- 0.1 and 3.9 +/- 0.2, respectively) and increased hyaluronic acid uptake (at 30 min, HMP + OKY vs SCS, HMP: 33.1 +/- 2.9% vs 13.9 +/- 3.6%, 18.6 +/- 2.4%, respectively). Liver histology also showed significant improvement in tissue edema and hepatocellular necrosis with OKY compared with HMP without OKY. CONCLUSION: The results demonstrate that TXA(2) is involved in the development of hepatocellular injury induced by HMP, and inhibition of TXA(2) synthesis during preservation and reperfusion protects liver hepatocytes and sinusoidal endothelial cells from injuries caused by prolonged HMP. SN - 1440-1746 UR - https://www.unboundmedicine.com/medline/citation/17645480/Inhibition_of_TXA_synthesis_with_OKY_046_improves_liver_preservation_by_prolonged_hypothermic_machine_perfusion_in_rats_ L2 - https://doi.org/10.1111/j.1440-1746.2007.05061.x DB - PRIME DP - Unbound Medicine ER -