环氧化酶-2抑制剂FK3311对犬全肝血管阻断模型缺血再灌注损伤的影响。
The effect of cyclooxygenase-2 inhibitor FK3311 on ischemia-reperfusion injury in a canine total hepatic vascular exclusion model.
作者信息
Sunose Y, Takeyoshi I, Ohwada S, Tsutsumi H, Iwazaki S, Kawata K, Kawashima Y, Tomizawa N, Matsumoto K, Morishita Y
机构信息
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
出版信息
J Am Coll Surg. 2001 Jan;192(1):54-62. doi: 10.1016/s1072-7515(00)00773-0.
BACKGROUND
Liver grafts from non-heart-beating donors inevitably suffer from warm ischemic injury. In these grafts, large quantities of inflammatory cytokines and arachidonic acid metabolites are induced, further aggravating injury. Cyclooxygenase (COX) is an intracellular enzyme that converts arachidonic acid into prostaglandin (PG)G2 and PGH2. COX has two isoforms: constitutive COX-1 and inducible COX-2. The aim of this study was to evaluate the effects of COX-2 inhibition by FK3311 (FK) on warm ischemic injury in a canine total hepatic vascular exclusion (THVE) model.
STUDY DESIGN
Sixteen mongrel adult dogs were studied. The portal triad of the hilum and the inferior vena cava above and below the liver was clamped for 1 hour. Splanchnic decompression was achieved by active splenofemorojugular bypass. The animals were divided into two groups. FK (1 mg/kg) was administered in the FK group (n = 8), and saline was administered in the control group (n = 8). Hepatic venous blood was collected to measure serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase (LDH), and hyaluronic acid levels. Serum thromboxane (Tx)B2 and 6-keto-PGF1alpha levels were also measured. Hepatic tissue blood flow was estimated simultaneously. Liver specimens were harvested for histologic study and polymorphonuclear neutrophils were counted.
RESULTS
Alanine aminotransferase, aspartate aminotransferase, and hyaluronic acid 2 and 6 hours after reperfusion and LDH 30 minutes and 2 and 6 hours after reperfusion were significantly (p < 0.05) lower in the FK group than in the control group. Hepatic tissue blood flow remained significantly (p < 0.05) higher in the FK group than in the control group 1, 2, and 6 hours after reperfusion. Histologic tissue damage was mild and polymorphonuclear neutrophil infiltration was significantly lower (p < 0.05) in the FK group than in the control group 1 and 6 hours after reperfusion. Thirty minutes after reperfusion, TxB2 was significantly reduced (p < 0.05) in the FK group, and 6-keto-PGF1alpha was not significantly lower.
CONCLUSIONS
FK protected against hepatic warm ischemia-reperfusion injury by marked inhibition of TxA2.
背景
来自非心跳供体的肝移植不可避免地会遭受热缺血损伤。在这些移植肝中，大量炎性细胞因子和花生四烯酸代谢产物被诱导产生，进一步加重损伤。环氧化酶（COX）是一种将花生四烯酸转化为前列腺素（PG）G2和PGH2的细胞内酶。COX有两种同工型：组成型COX-1和诱导型COX-2。本研究的目的是评估FK3311（FK）抑制COX-2对犬全肝血管阻断（THVE）模型热缺血损伤的影响。
研究设计
对16只成年杂种犬进行研究。钳夹肝门部的门静脉三联以及肝脏上下的下腔静脉1小时。通过主动脾-股-颈静脉旁路实现内脏减压。将动物分为两组。FK组（n = 8）给予FK（1 mg/kg），对照组（n = 8）给予生理盐水。采集肝静脉血以测定血清丙氨酸氨基转移酶、天冬氨酸氨基转移酶、乳酸脱氢酶（LDH）和透明质酸水平。还测定血清血栓素（Tx）B2和6-酮-前列腺素F1α水平。同时估计肝组织血流量。获取肝脏标本进行组织学研究并计数多形核中性粒细胞。
结果
FK组再灌注后2小时和6小时的丙氨酸氨基转移酶、天冬氨酸氨基转移酶和透明质酸水平以及再灌注后30分钟、2小时和6小时的LDH水平均显著低于对照组（p < 0.05）。再灌注后1小时、2小时和6小时，FK组的肝组织血流量仍显著高于对照组（p < 0.05）。组织学组织损伤较轻，再灌注后1小时和6小时，FK组的多形核中性粒细胞浸润显著低于对照组（p < 0.05）。再灌注后30分钟，FK组的TxB2显著降低（p < 0.05），而6-酮-前列腺素F1α无显著降低。
结论
FK通过显著抑制TxA2预防肝热缺血-再灌注损伤。
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