Projectdetails

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To study the loss of epithelial barrier function in human cholangiocytes in various perfusion solutions.

Keywords:
liver transplantation ischemia/reperfusion injury preservation fluids

Researchers:
Dr. S.C.D. van IJzendoorn
Prof. dr. R.J. Porte
drs. A.C. Westerkamp

Nature of the research:
Laboratory research in the field of surgery (liver transplantations) and cell biology

Fields of study:
cell biology surgery

Background / introduction
During the period of organ preservation with simple cold storage, the liver and bile ducts are exposed to a long period of cooling and ischemia. Especially, the bile ducts are extremely vulnerable for ischemia during the cooling period with the development of non-anastomotic strictures (NAS) as consequence (1). Patients with NAS frequently suffer from episodes of cholangitis and in most cases a retransplantation is the only curative treatment. (1)
It seems to be that the current method of organ preservation is far from sufficient to protect the biliary epithelium regarding the high rates of NAS. (2)
A couple of older studies have mimicked ischemia and ATP depletion in cholangiocyte cell (bile duct cells) culture studies. The authors showed that loss of cellular polarity, reduction in de number of microvilli and loss of membrane proteins for bile secretion is related to ischemia and they suggest that these cell changes could be associated to postischemic injury during organ preservation before OLT (3,4) Nevertheless, the influence of various preservation fluids during ischemia/cooling on the barrier function of cholangiocytes is rather unknown. Understanding how the mechanism of epithelial dysfunction in preservation fluids works, could lead to better organ preservation methods as adjustments of the current preservation solutions.
Research question / problem definition
Is there a difference in injury mechanism between various perfusion solutions in the epithelial barrier of cholangiocytes?
Workplan
Working with human cholagiocytes in cell cultures. Evaluation of cell and barrier function of cholangiocytes in different organ perfusion fluids (UW/HTK/Celsior).
References
(1) Op den Dries S, Sutton ME, Lisman T, Porte RJ. Protection of bile ducts in liver transplantation: looking beyond ischemia. Transplantation 2011 Aug 27;92(4):373-379.
(2) Karimian N, Op den Dries S, Porte RJ. The origin of biliary strictures after liver transplantation: is it the amount of epithelial injury or insufficient regeneration that counts? J Hepatol 2013 Jun;58(6):1065-1067.
(3) Doctor RB, Dahl RH, Salter KD, Fouassier L, Chen J, Fitz JG. ATP depletion in rat cholangiocytes leads to marked internalization of membrane proteins. Hepatology 2000 May;31(5):1045-1054.
(4) Doctor RB, Dahl RH, Salter KD, Fitz JG. Reorganization of cholangiocyte membrane domains represents an early event in rat liver ischemia. Hepatology 1999 May;29(5):1364-1374.
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