Role of Kupffer cells in the survival after rat liver transplantation with long portal vein clamping times.
Applying the orthotopic rat liver transplantation (ORLT) model, postoperative survival has been shown to be mainly dependent on the portal vein clamping time (PVCT). It was hypothesized that prolonged intestinal congestion was responsible for the activation of Kupffer cells (KC) with overproduction of TNF, secondary to splanchnic endotoxin accumulation and release on reperfusion. The role of KCs was directly investigated in the context of long PVCTs by eliminating them (using liposome-encapsulated dichloromethylene diphosphonate), by preventing their activation (using a calcium channel blocker, nisoldipine) and by inhibiting TNF production (using thalidomide). Livers from different groups of rats were transplanted following 24-h cold preservation in the UW solution with long PVCTs (from 18-21 min). KCs depletion, preservation with nisoldipine and pretreatment with thalidomide significantly improved survival in conditions using long PVCTs. KC depletion and nisoldipine preservation had no effect on liver enzymes or pathological findings while lung injury was significantly improved. The present data confirm that, in the context of ORLT with long PVCTs, KCs are directly responsible for the systemic endotoxin-like shock syndrome and their effect is mediated through overproduction of TNF.
Urata
K
K
Research Centre-Hôpital Saint-Luc, CHUM, 264 East René Lévesque Blvd, Montréal, QC, H2X 1P1, Canada.
Brault
A
A
Rocheleau
B
B
Huet
P M
PM
D000241:Adenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); D000493:Allopurinol; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002452:Cell Count; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology; D003080:Cold Temperature; D003250:Constriction; D005978:Glutathione; D006085:Graft Survival; D006498:Hepatectomy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007328:Insulin; D007511:Ischemia; D007728:Kupffer Cells / Q000187:drug effects / Q000502:physiology*; D008081:Liposomes; D008099:Liver / Q000098:blood supply / Q000473:pathology; D016031:Liver Transplantation / Q000379:methods* / Q000473:pathology; D008168:Lung / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D015737:Nisoldipine / Q000494:pharmacology; D019188:Organ Preservation Solutions; D011169:Portal Vein; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control*; D011887:Raffinose; D051381:Rats; D011917:Rats, Inbred Lew; D017382:Reactive Oxygen Species; D012769:Shock / Q000209:etiology / Q000517:prevention & control*; D013792:Thalidomide / Q000494:pharmacology; D013997:Time Factors; D009927:Tissue and Organ Procurement / Q000379:methods*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism
D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D007328:Insulin; D008081:Liposomes; D019188:Organ Preservation Solutions; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C055206:University of Wisconsin-lactobionate solution; D004002:Clodronic Acid; D019830:Adenosine-5'-(N-ethylcarboxamide); D015737:Nisoldipine; D013792:Thalidomide; D000493:Allopurinol; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose