Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Transplantation. 2010 Feb 15;89(3):291-8. doi: 10.1097/TP.0b013e3181c99185.
Steatotic liver grafts are excluded for partial liver transplantation because of increased risk of primary nonfunction. Mechanisms underlying the failure of fatty partial liver grafts (FPG) remain unknown. This study investigated whether inducible nitric oxide synthase (iNOS) plays a role in failure of FPG.
Fatty livers were induced by feeding rats a high-fat high-fructose diet for 2 weeks. Hepatic triglyceride was approximately 9-fold higher in rats fed the high-fat high-fructose diet than those fed a low-fat low-fructose diet. Lean and fatty liver explants were reduced in size ex vivo to approximately one third, stored in the University of Wisconsin cold storage solution for 2 hr, and implanted.
Posttransplantational hepatic iNOS expression and reactive nitrogen species (RNS) formation (nitrite and nitrate levels and 3-nitrotyrosine adducts) increased more profoundly in FPG than in lean partial grafts (LPG). Serum alanine aminotransferase and bilirubin were 2- and 5.5-fold higher after transplantation of FPG than LPG. 5-Bromo-2'-deoxyuridine incorporation was 25% in LPG but only 5% in FPG, and graft weight increased by 64% in LPG while remaining unchanged in FPG. All rats that received FPG died, whereas all those receiving LPG survived. N-(1-naphtyl)ethylendiamine dihydrochloride (5 microM), a specific iNOS inhibitor, largely blunted the production of RNS, prevented the increase of alanine aminotransferase and bilirubin, restored liver regeneration, and improved survival of FPG. Mitochondrial cytochrome c oxidase-IV, ATP synthase-beta, and NADH dehydrogenase-3 decreased markedly in FPG, and these effects were blocked by N-(1-naphtyl)ethylendiamine dihydrochloride.
Thus, hepatic steatosis causes failure of partial liver grafts, most likely by increasing RNS that leads to mitochondrial damage and dysfunction.
由于原发性无功能的风险增加，脂肪性供肝被排除在部分肝移植之外。脂肪性部分肝移植物（FPG）衰竭的机制尚不清楚。本研究探讨诱导型一氧化氮合酶（iNOS）是否在 FPG 衰竭中起作用。
通过给大鼠喂食高脂肪高果糖饮食 2 周来诱导脂肪肝。高脂肪高果糖饮食组大鼠肝组织三酰甘油含量约为低脂低果糖饮食组的 9 倍。将瘦肝和脂肪肝标本离体缩小至约三分之一大小，用威斯康星大学冷保存液保存 2 小时，然后植入。
FPG 比 lean partial grafts（LPG）的肝移植后 iNOS 表达和活性氮（RNS）形成（亚硝酸盐和硝酸盐水平和 3-硝基酪氨酸加合物）增加更明显。FPG 移植后血清丙氨酸氨基转移酶和胆红素分别比 LPG 高 2 倍和 5.5 倍。LPG 中 5-溴-2'-脱氧尿苷的掺入率为 25%，而 FPG 中仅为 5%，LPG 中移植物重量增加 64%，而 FPG 中不变。所有接受 FPG 的大鼠均死亡，而所有接受 LPG 的大鼠均存活。N-（1-萘基）乙二胺二盐酸盐（5μM），一种特异性 iNOS 抑制剂，大大减少了 RNS 的产生，防止了丙氨酸氨基转移酶和胆红素的增加，恢复了肝再生，并提高了 FPG 的存活率。FPG 中细胞色素 c 氧化酶-IV、ATP 合酶-β 和 NADH 脱氢酶-3 明显减少，这些作用被 N-（1-萘基）乙二胺二盐酸盐阻断。
因此，肝脂肪变性导致部分肝移植物衰竭，很可能是通过增加 RNS 导致线粒体损伤和功能障碍。
