| Co-Investigator(Kenkyū-buntansha) |
ORII Takashi Tohoku Univ., School of Medicine Hospital, Research Associate, 医学部・附属病院, 助手 (20282048)
DOI Hideyuki Tohoku Univ., School of Medicine Hospital, Lecturer, 医学部・附属病院, 講師 (90188839)
FUJIMORI Keisei Tohoku Univ., Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (50238622)
KUROKAWA Yoshimochi Tohoku Univ., School of Medicine Hospital, Lecturer, 医学部・附属病院, 講師 (80215087)
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| Budget Amount *help |
¥16,300,000 (Direct Cost: ¥16,300,000)
Fiscal Year 2000: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1999: ¥14,700,000 (Direct Cost: ¥14,700,000)
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| Research Abstract |
[Background and Purpose] Microcirculatory disturbance is a main obstacle to liver transplantation (LTx) from non-heart beating donors (NHBD) and it is attributed to a deterioration of sinusoidal endothelial cells (SEC) and sinusoidal narrowing. We examined roles of Kupffer cells (KC) in the sinusoidal microcirculation of the graft of NHBD, focusing on NF-κB and cytokines and eicosanoids. We also investigated effects of KC elimination and cytokine suppression on LTx from agonal NHBD, [Materials/Methods] A) Livers of Wistar rat were isolated and perfused for 60 minutes with Krebs-Henseleit bicarbonate buffer. Animals were divided into four groups as follows (n=6) : control group, liver was perfused without preservation ; HB group, livers were perfused after 6 hr cold preservation ; NHB group, liver from NHBD was perfused after cold preservation ; KE group, rats were pretreated with liposome-encapsulated dichloromethlene diphoshonate to eliminate KC.Liver from NHBD was perfused after cold
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preservation. NF-κB, cytokines (TNFα, IL-1β, IL-6), eicosanoids (TXA2, 6-ket-PGF1α, LTB4), AST and LDH were measured. B) Pigs were allocated to five groups (n=6) : NHB group, liver graft from NHBD was transplanted ; NM group, graft from NHBD was rinsed with nafamostat mesilate (NM) rinse solution ; KC *inated group, KC eliminated graft from NHBD was transplanted ; KC eliminated+NM rinse group, KC eliminated graft from NHBD was transplanted with rinsing NM rinse solution ; cytokine suppression group, TNFθ and IL1β were suppressed and PGE1was administered before and after liver Tx from NHBD.[Results] A) NF-κB activity of the NHB group was significantly higher than those of the other groups. In KE group, NF-κB activity was suppressed as same level as in control group, In KE group, cytokine and eicosanoid levels were suppressed and sinusoidal structures were preserved well. B) Both in KC eliminated +NM rinse and cytokine suppression groups, four of five recipients survived. After reperfusion, it was histologically demonstrated that elimination of Kupffer cells prevented SEC deterioration and NM rinse prevented sinusoidal narrowing. The energy charge of liver tissue recovered in all groups except NHB group. [Conclusions] KC activities have an important roll in the disturbance of sinusoidal microcirculation in Tx from NHBD.Modulation of KC is a key for success in liver transplantation from NHBD and it is important to prevent microcirculatory disturbance of SEC deterioration and sinusoidal narrowing. Combination therapy consisting of suppression of KC activities and NM rinse will be able to prevent primary graft non-function in liver grafts from agonal NHBD. Less
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