Winlaw D S, Schyvens C G, Smythe G A, Du Z y, Rainer S P, Keogh A M, Mundy J A, Lord R S, Spratt P M, MacDonald P S
Department of Cardiopulmonary Transplantation, St. Vincent's Hospital, Sydney, Australia.
Transplantation. 1994 Nov 15;58(9):1031-6. doi: 10.1097/00007890-199411150-00010.
Cytokine induction of calcium-independent nitric oxide synthase is associated with production of large amounts of nitric oxide (NO). NO is a free radical that is rapidly degraded to nitrite and nitrate. Measurement of plasma and urinary nitrate is an indirect marker of NO production and previous studies have demonstrated that plasma nitrate rises with allograft rejection. The purpose of this study was to examine the temporal relationship between the rise in urinary nitrate excretion and the onset of graft rejection, and to determine the effect of conventional immunosuppression on nitrate excretion. The heterotropic model of cardiac transplantation in the rat was used, with Brown-Norway to Lewis allografts and Lewis to Lewis isograft controls. Twenty-four-hour urine specimens were collected before and after transplantation. Urinary nitrate excretion was measured by gas chromatography/mass spectrometry. Each group was treated with (1) no immunosuppression, (2) dexamethasone (3 mg/kg), or (3) CsA (10 mg/kg) on days 0, 1, and 2. Time to rejection for untreated allografts was 5.1 +/- 0.1 days, extending to 8.4 +/- 0.5 and 9.6 +/- 0.4 days with dexamethasone and CsA treatment, respectively. There was a significant rise in nitrate excretion on days 4, 7, and 9 for control, dexamethasone-treated, and CsA-treated allografts, respectively, preceding evidence of rejection. Untreated allograft rejection was associated with a peak in nitrate excretion 8 times that of basal excretion by isografts. Treatment of the allografts with dexamethasone and CsA significantly attenuated peak nitrate excretion compared with untreated allografts with a only a 2- to 3-fold rise preceding rejection. Results indicate that allograft rejection is associated with a dramatic increase in peak urinary nitrate excretion that is attenuated by standard immunosuppressive therapy. An increase in nitrate excretion precedes evidence of graft rejection, and may serve as a noninvasive marker of graft rejection.
细胞因子诱导的钙非依赖性一氧化氮合酶与大量一氧化氮（NO）的产生有关。NO是一种自由基，会迅速降解为亚硝酸盐和硝酸盐。血浆和尿硝酸盐的测量是NO产生的间接指标，先前的研究表明，同种异体移植排斥反应时血浆硝酸盐水平会升高。本研究的目的是检查尿硝酸盐排泄增加与移植排斥反应发生之间的时间关系，并确定传统免疫抑制对硝酸盐排泄的影响。采用大鼠心脏移植的异位模型，以布朗-挪威大鼠到刘易斯大鼠的同种异体移植以及刘易斯大鼠到刘易斯大鼠的同基因移植作为对照。在移植前后收集24小时尿液样本。通过气相色谱/质谱法测量尿硝酸盐排泄量。每组在第0、1和2天接受以下处理：（1）不进行免疫抑制，（2）地塞米松（3mg/kg），或（3）环孢素A（10mg/kg）。未治疗的同种异体移植的排斥时间为5.1±0.1天，用地塞米松和环孢素A治疗后分别延长至8.4±0.5天和9.6±0.4天。在对照、地塞米松治疗和环孢素A治疗的同种异体移植中，分别在第4、7和9天出现硝酸盐排泄显著增加，早于排斥反应的证据。未治疗的同种异体移植排斥反应与硝酸盐排泄峰值相关，该峰值是同基因移植基础排泄量的8倍。与未治疗的同种异体移植相比，用地塞米松和环孢素A治疗同种异体移植显著减弱了硝酸盐排泄峰值，排斥反应前仅升高2至3倍。结果表明，同种异体移植排斥反应与尿硝酸盐排泄峰值的显著增加有关，而标准免疫抑制疗法可减弱这种增加。硝酸盐排泄增加早于移植排斥反应的证据，可能作为移植排斥反应的非侵入性标志物。
