Mangino M J, Jendrisak M D, Brunt E, Anderson C B
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110.
Transplantation. 1988 May;45(5):902-7. doi: 10.1097/00007890-198805000-00012.
The effects of the dual cyclooxygenase-lipoxygenase inhibitor 3-amino-1-(m[trifluoromethyl]phenyl)-2-pyrazoline (BW755C) (10 mg/kg, p.o., b.i.d.) on renal blood flow, glomerular filtration rate (GFR), and eicosanoid production were examined in anesthetized dogs that had undergone unilateral renal allotransplantation. Rejecting renal allograft blood flow significantly declined over a 5-day period compared to the nonrejecting native kidney. In animals treated with BW755C, renal allograft blood flow was maintained over the postoperative 5-day period at levels comparable to blood flow to the native kidneys. While GFR and urine flow progressively declined in the rejecting kidney, treatment with BW755C prevented the fall in GFR and even augmented urine flow. Allograft renal cortical production or thromboxane B2 (TXB2) and leukotriene B4 (LTB4) in animals treated with BW755C was not significantly different than production by the native contralateral kidneys. Furthermore, BW755C reduced cellular infiltration and tissue damage in allografts compared to nontreated renal allografts. The selective cyclooxygenase inhibitor, indomethacin (5 mg/kg, p.o., b.i.d.) exerted no effect on renal allograft GFR or urine output but reduced allograft blood flow after 4 days compared to nontreated allografts. In conclusion, inhibition of arachidonate cyclooxygenase and lipoxygenase metabolism improves renal allograft function and reduces tissue damage while selective inhibition of the cyclooxygenase pathway does not improve renal allograft function. These data indicate that products of arachidonate-lipoxygenase metabolism potentiate the loss of renal function and tissue destruction associated with renal allograft rejection.
在接受单侧肾同种异体移植的麻醉犬中，研究了双重环氧化酶-脂氧合酶抑制剂3-氨基-1-（间[三氟甲基]苯基）-2-吡唑啉（BW755C）（10毫克/千克，口服，每日两次）对肾血流量、肾小球滤过率（GFR）和类花生酸生成的影响。与未发生排斥反应的天然肾脏相比，发生排斥反应的肾同种异体移植血流量在5天内显著下降。在用BW755C治疗的动物中，肾同种异体移植血流量在术后5天内维持在与天然肾脏血流量相当的水平。虽然排斥反应的肾脏中GFR和尿流量逐渐下降，但BW755C治疗可防止GFR下降，甚至增加尿流量。用BW755C治疗的动物中，同种异体移植肾皮质血栓素B2（TXB2）和白三烯B4（LTB4）的生成与对侧天然肾脏的生成无显著差异。此外，与未治疗的肾同种异体移植相比，BW755C减少了同种异体移植中的细胞浸润和组织损伤。选择性环氧化酶抑制剂吲哚美辛（5毫克/千克，口服，每日两次）对肾同种异体移植GFR或尿量无影响，但与未治疗的同种异体移植相比，4天后降低了同种异体移植血流量。总之，抑制花生四烯酸环氧化酶和脂氧合酶代谢可改善肾同种异体移植功能并减少组织损伤，而选择性抑制环氧化酶途径并不能改善肾同种异体移植功能。这些数据表明，花生四烯酸-脂氧合酶代谢产物会加剧与肾同种异体移植排斥相关的肾功能丧失和组织破坏。
