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Current Hypothesis of Preservation Injury of Hepatic Grafts (Mini Review)

The Skeptik, 2017, Vol. 3, pgs. (6-8)

Kukan M. Slovak Medical University, emeritus, Bratislava, Slovakia

The liver comprises of several cell types. Hepatocytes, nonparenchymal cells - endothelial cells, Kupffer cells, and hepatic stellate cells.

Ealier studies (from 1997 up to 2001) showed that Kupffer cell activation and endothelial cell damage plays key roles of hepatic graft injury after cold ischemia-reperfusion of rat livers  (1-6). This fact was further supported by a finding that endothelial cell damage can be prevented by anti-angionetic agents (7).

However, our study (from 1997)  in isolated, a blood-free reperfused rat liver model, showed that Kupffer cells played a minor role in cold ischemia-reperfusion injury, because liver function was not altered by Kupffer cell depletion (8). This led us to review the role of hepatocytes (liver parenchymal cells) in reperfusion of hepatic grafts (9). We clearly analyzed that energy stores, which are derived chiefly from hepatocytes plays a major role in hepatic graft function (9).   

Further, we found that stores of energy (ATP, ADP, AMP) can be repleted by short-therm warm reperfusion even after 18 hours of cold storage of rat livers (10).
ATP synthesis prior to liver transplantation can be also done by hypothermic oscillating liver perfusion. (11, 12). In addition, protective effect of energy repletion into hepatic grafts was also found in a blood-reperfused model of cold ischemia-reperfusion injury of rat livers (13). 
Finally, ATP stores can be repleted by machine perfusion of hepatic grafts (see for review (14)). Repletion of tissue energy by machine perfusion was also confirmed in multicentric study in human liver transplantation model (15).

Thus, current hypothesis of preservation hepatic graft injury indicates that Kupffer cells and endothelial liver cells have minimal effects, while repletion of energy stores, (which are mainly derived from hepatocytes) have a pivotal role in primary graft function in the recipient. There is also a strong hypothesis that hepatic stellate cells can contribute to preservation-reperfusion injury (16), especially during several (hours/days) post transplantation surgery.  


1. Schemmer P, Enomoto N, Bradford BU, Bunzendahl H, Raleigh JA, Lemasters JJ, Thurman RG. Activated Kupffer cells cause a hypermetabolic state after gentle in situ manipulation of liver in rats.
Am J Physiol Gastrointest liver Physiol. 2001 Jun;280(6):G1076-82.

2.Arai M, Thurman RG, Lemasters JJ. Ischemic preconditioning of rat livers against cold storage-reperfusion injury: role of nonparenchymal cells and the phenomenon of heterologous preconditioning. Liver Transpl. 2001 Apr;7(4):292-9.

3. Arai M, Thurman RG, Lemasters JJ.  Contribution of adenosine A(2) receptors and cyclic adenosine monophosphate to protective ischemic preconditioning of sinusoidal endothelial cells against Storage/Reperfusion injury in rat livers. Hepatology. 2000 Aug;32(2):297-302

4. Schemmer P, Schoonhoven R, Swenberg JA, Bunzendahl H, Raleigh JA, Lemasters JJ, Thurman RG. Gentle organ manipulation during harvest as a key determinant of survival of fatty livers after transplantation in the rat. Transpl Int. 1999;12(5):351-9

5 Schemmer P, Schoonhoven R, Swenberg JA, Bunzendahl H, Thurman RG.
Gentle in situ liver manipulation during organ harvest decreases survival after rat liver transplantation: role of Kupffer cells.  Transplantation. 1998 Apr 27;65(8):1015-20.

6. Lemasters JJ, Thurman RG. Reperfusion injury after liver preservation for transplantation. Annu Rev Pharmacol Toxicol. 1997;37:327-38. Review.

7. Gao W, Washington MK, Bentley RC, Clavien PA. Antiangiogenic agents protect liver sinusoidal lining cells from cold preservation injury in rat liver transplantation. Gastroenterology. 1997 Nov;113(5):1692-700.

8. Kukan M, Vajdová K, Horecký J, Nagyová A, Mehendale HM, Trnovec T. Effects of blockade of Kupffer cells by gadolinium chloride on hepatobiliary function in cold ischemia-reperfusion injury of rat liver. Hepatology. 1997 Nov;26(5):1250-7.

9. Kukan M, Haddad PS. Role of hepatocytes and bile duct cells in preservation-reperfusion injury of liver grafts. Liver Transpl. 2001 May;7(5):381-400. Review.

10. Vajdová K, Smreková R, Mislanová C, Kukan M, Lutterová M. Cold-preservation-induced sensitivity of rat hepatocyte function to rewarming injury and its prevention by short-term reperfusion. Hepatology. 2000 Aug;32(2):289-96.

11. Dutkowski P, Schönfeld S, Heinrich T, Watzka M, Winkelbach V, Krysiak M, Odermatt B, Junginger T. Reduced oxidative stress during acellular reperfusion of the rat liver after hypothermic oscillating perfusion. Transplantation. 1999 Jul 15;68(1):44-50.

12.Dutkowski P, Odermatt B, Heinrich T, Schönfeld S, Watzka M, Winkelbach V,  Krysiak M, Junginger T. Hypothermic oscillating liver perfusion stimulates ATP synthesis prior to transplantation. J Surg Res. 1998 Dec;80(2):365-72.

13. Kukan M, Vajdová K, Lutterová M, Kristek F, Kebis A, Kuba D, Horecký J.  Improvement of rat liver function by energy repletion after the preservation period: implications for hepatic graft management. Cryobiology. 2001 Dec;43(4):303-9.

14. Dutkowski P, de Rougemont O, Clavien PA. Machine perfusion for 'marginal' liver grafts. Am J Transplant. 2008 May;8(5):917-24. Review.

15. Dutkowski P, Polak WG, Muiesan P, Schlegel A, Verhoeven CJ, Scalera I, DeOliveira ML, Kron P, Clavien PA. First Comparison of Hypothermic Oxygenated PErfusion Versus Static Cold Storage of Human Donation After Cardiac Death Liver Transplants: An International-matched Case Analysis. Ann Surg. 2015 Nov;262(5):764-70; discussion 770-1.

16. Stewart RK, Dangi A, Huang C, Murase N, Kimura S, Stolz DB, Wilson GC, Lentsch AB, Gandhi CR. A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury.J Hepatol. 2014 Feb;60(2):298-305.