Pieper Galen M, Nilakantan Vani, Hilton Gail, Zhou Xianghua, Khanna Ashwani K, Halligan Nadine L N, Felix Christopher C, Kampalath Bal, Griffith Owen W, Hayward Mike A, Roza Allan M, Adams Mark B
Division of Transplant Surgery, Department of Surgery, Cardiovascular Center, Medical College of Wisconsin, Milwaukee 53226, USA.
Am J Physiol Heart Circ Physiol. 2004 Feb;286(2):H525-34. doi: 10.1152/ajpheart.00356.2003.
We examined the efficacy and mechanism of action of N(6)-(1-iminoethyl)-L-lysine (L-NIL), a highly selective inhibitor of inducible nitric oxide (NO) synthase (iNOS), on acute cardiac transplant rejection. L-NIL produced a concentration-dependent attenuation of plasma NO by-products and a decrease in nitrosylation of heme protein without altering protein levels of iNOS. At postoperative day 4, L-NIL did not alter the increased binding activities for transcription factors nuclear factor-kappaB and activator protein-1. Whereas L-NIL decreased inflammatory cell infiltration, graft survival was only prolonged at the dose of 1.0 microg/ml that incompletely blocked NO production. Higher L-NIL concentrations (30 and 60 microg/ml) ablated the increased NO production but failed to improve graft survival and even potentiated NF-kappaB binding activity examined at day 6. Alloimmune activation indicated by increased cytokine gene expression for interferon-gamma, interleukin-6, and interleukin-10 was inhibited in grafts only by treatment with 1.0 microg/ml L-NIL. These findings suggest a complex role of NO in acute cardiac allograft rejection. Partial inhibition of iNOS is beneficial to graft survival, whereas total ablation may oppose any benefits to graft survival. These studies have important implications in understanding the dual role of NO in acute rejection and help to reconcile discrepancies in the literature.
我们研究了N(6)-(1-亚氨基乙基)-L-赖氨酸（L-NIL）（一种诱导型一氧化氮合酶（iNOS）的高度选择性抑制剂）对急性心脏移植排斥反应的疗效和作用机制。L-NIL呈浓度依赖性地降低血浆一氧化氮副产物，并降低血红素蛋白的亚硝化作用，而不改变iNOS的蛋白水平。在术后第4天，L-NIL并未改变转录因子核因子-κB和活化蛋白-1增加的结合活性。虽然L-NIL减少了炎症细胞浸润，但仅在1.0微克/毫升剂量时延长了移植物存活时间，该剂量并未完全阻断一氧化氮的产生。更高浓度的L-NIL（30和60微克/毫升）消除了增加的一氧化氮产生，但未能改善移植物存活，甚至在第6天增强了检测到的核因子-κB结合活性。仅用1.0微克/毫升L-NIL处理可抑制移植物中由干扰素-γ、白细胞介素-6和白细胞介素-10细胞因子基因表达增加所表明的同种免疫激活。这些发现提示一氧化氮在急性心脏同种异体移植排斥反应中起复杂作用。部分抑制iNOS有利于移植物存活，而完全消除可能对移植物存活无任何益处。这些研究对于理解一氧化氮在急性排斥反应中的双重作用具有重要意义，并有助于调和文献中的差异。
