Nakache R, Rudick V, Fiodorov D, Klausner J M, Almogy N, Karckevski E, Weinbroum A A
Department of Anesthesiology and Critical Care Medicine, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
Transplantation. 1999 Dec 15;68(11):1651-60. doi: 10.1097/00007890-199912150-00008.
Cyclosporine (CsA) is an essential posttransplantation immunosuppressive drug. It may cause hepatotoxicity, mostly cholestasis, by unknown mechanism. CsA causes nephrotoxicity mainly by increased vascular resistance. We investigated the effects of CsA on the peribiliary capillary plexus, in an isolated, dually perfused (i.e., via the hepatic artery and the portal vein) rat liver preparation.
After 30 min of stabilization with optimal flow (4 ml/min/g liver), four liver groups were perfused (control, n=5 each) and four groups were hypoperfused (n=5 each, 1 ml/min/g) for 120 min. This was followed by a 30-min optimal reperfusion phase, during which the controls and the hypoperfused groups were injected (60 sec) via the hepatic artery with CsA at high (3 mg/kg body weight in 1 ml) or low dose (0.03 mg/kg), cremophore (130 mg/kg), or saline (1 ml). A ninth group (n=5) underwent 2-hr ischemia and 30-min reperfusion to standardize liver damage. Dark nonradioactive microspheres (approximately 10 microm diameter) were injected via the hepatic artery 15 min after drug or saline injection.
Neither of the two CsA doses, nor cremophore controls, nor hypoperfusion alone caused entrapment of microspheres in the peribiliary circulation as assessed by light microscopy; perfusion pressures and resistances were also not altered. Significant arteriolar impaction and vasculature engorgement occurred in the hypoperfused plus high-dose CsA livers; hypoperfusion plus low-dose CsA or cremophore groups were minimally tainted. Vascular notable obstruction was associated with 15-40% increase in portal and arterial perfusion pressures and resistances, 50% decrease in oxygen extraction, and increase in lactate/pyruvate ratio, hepatocellular damage, and wet-to-dry weight ratio. Such findings were superior to those detected in the ischemic livers.
Acute single high-dose CsA injection, but not low-dose or cremophore, if combined with decreased flow, alters hepatic microcirculatory resistance. Possible correlations between such changes and clinical implications in organ transplantation are discussed.
环孢素（CsA）是一种移植后必不可少的免疫抑制药物。它可能通过未知机制导致肝毒性，主要是胆汁淤积。CsA主要通过增加血管阻力引起肾毒性。我们在一种分离的、双重灌注（即通过肝动脉和门静脉）的大鼠肝脏标本中研究了CsA对肝内胆小管周围毛细血管丛的影响。
在以最佳流量（4毫升/分钟/克肝脏）稳定30分钟后，对四组肝脏进行灌注（对照组，每组n = 5），对四组肝脏进行低灌注（每组n = 5，1毫升/分钟/克），持续120分钟。随后是30分钟的最佳再灌注期，在此期间，通过肝动脉向对照组和低灌注组注射（60秒）高剂量（1毫升中含3毫克/千克体重）或低剂量（0.03毫克/千克）的CsA、聚氧乙烯蓖麻油（130毫克/千克）或生理盐水（1毫升）。第九组（n = 5）进行2小时缺血和30分钟再灌注以标准化肝损伤。在注射药物或生理盐水15分钟后，通过肝动脉注射深色非放射性微球（直径约10微米）。
通过光学显微镜评估，两种CsA剂量、聚氧乙烯蓖麻油对照组以及单独的低灌注均未导致微球在肝内胆小管周围循环中滞留；灌注压力和阻力也未改变。在低灌注加高剂量CsA的肝脏中出现了显著的小动脉阻塞和血管充血；低灌注加低剂量CsA或聚氧乙烯蓖麻油组仅有轻微影响。明显的血管阻塞与门静脉和动脉灌注压力及阻力增加15% - 40%、氧摄取减少50%、乳酸/丙酮酸比值升高、肝细胞损伤以及湿重与干重比值增加有关。这些发现优于在缺血肝脏中检测到的结果。
急性单次高剂量注射CsA（而非低剂量或聚氧乙烯蓖麻油），若与血流减少相结合，会改变肝脏微循环阻力。讨论了这些变化与器官移植临床意义之间可能的相关性。
