Anaya-Prado Roberto, Toledo-Pereyra Luis H, Guo R F, Reuben J, Ward Peter A, Walsh J
Borgess Research Institute, Trauma, Surgery Research Sciences and Molecular Biology, Kalamazoo, Michigan 49048, USA.
J Invest Surg. 2003 Sep-Oct;16(5):247-61.
We investigated the role of nitric oxide (NO) in its ability to reduce liver injury in an animal model of hemorrhagic shock (HS). Ninety-six Sprague-Dawley rats weighing 250 to 300 g were divided in 6 groups (n = 16 per group) that included treatment at the beginning of resuscitation with normal saline (groups 1, 3) sodium nitroprusside (NP) (0.5 mg/kg) (groups 2, 4) L-arginine (300 mg/kg) (group 5), and L-N6-(1-iminoethyl) lysine (L-NIL, 40 mg/kg) (group 6). The experimental model of HS consisted of the withdrawal of 3 mL blood per 100 g in a 15-min period, tail amputation (75%), and drug administration at 30 min. This was followed by fluid resuscitation (FR) with lactated Ringer's (LR) solution to reach a mean arterial pressure (MAP) of 40 mm Hg, then a hospital phase of 60 min with hemostasis and FR with LR solution to reach a MAP of 70 mm Hg with a 3-day observation phase. NP, L-Arginine, and L-NIL significantly reduced fluid requirements for resuscitation (p =.0001) as well as significantly increased MAP after resuscitation from hemorrhage. We also observed an improved statistically significant difference (p =.001) in tests demonstrating less hepatic injury and histology damage. The mRNA expression of cytokines in the liver (interleukin [IL]-1alpha, IL-beta1, tumor necrosis factor [TNF]beta, IL-3, IL-4, IL-5, IL-6, IL-10, TNFalpha, IL-2, interferon [IFN]gamma) was reduced by NP treatment, L-arginine, and L-NIL. These data suggest that excess NO mediates hemorrhage-induced liver injury and that the suppression of inducible nitric oxide synthase (iNOS)-generated NO bioavailability with the NO donor sodium nitroprusside may reduce the pathophysiologic consequences of severe hemorrhage. This effect could be possibly related to the scavenging of to superoxide radicals (O2-) or the blockade of the deleterious effects of TNF and other inflammatory cytokines. The protective action noted with L-arginine cannot be fully explained within the context of this article, although it could be most likely associated with the supplementation of eNOS-generated NO.
我们研究了一氧化氮（NO）在出血性休克（HS）动物模型中减轻肝损伤能力方面的作用。将96只体重250至300克的Sprague-Dawley大鼠分为6组（每组n = 16），包括在复苏开始时用生理盐水治疗（第1、3组）、硝普钠（NP）（0.5毫克/千克）治疗（第2、4组）、L-精氨酸（300毫克/千克）治疗（第5组）以及L-N6-（1-亚氨基乙基）赖氨酸（L-NIL，40毫克/千克）治疗（第6组）。HS实验模型包括在15分钟内每100克体重抽取3毫升血液、尾部截肢（75%），并在30分钟时给药。随后用乳酸林格氏（LR）溶液进行液体复苏（FR）以使平均动脉压（MAP）达到40毫米汞柱，然后进入60分钟的住院阶段，进行止血并继续用LR溶液进行FR以使MAP达到70毫米汞柱，并进行为期3天的观察阶段。NP、L-精氨酸和L-NIL显著降低了复苏所需的液体量（p = 0.0001），并在出血复苏后显著提高了MAP。我们还观察到在显示肝损伤和组织学损伤较轻的测试中，统计学上有显著改善（p = 0.001）。NP治疗、L-精氨酸和L-NIL降低了肝脏中细胞因子的mRNA表达（白细胞介素[IL]-1α、IL-β1、肿瘤坏死因子[TNF]β、IL-3、IL-4、IL-5、IL-6、IL-10、TNFα、IL-2、干扰素[IFN]γ）。这些数据表明，过量的NO介导出血性肝损伤，并且用NO供体硝普钠抑制诱导型一氧化氮合酶（iNOS）产生的NO生物利用度可能会减轻严重出血的病理生理后果。这种作用可能与清除超氧阴离子自由基（O2-）或阻断TNF和其他炎性细胞因子的有害作用有关。尽管L-精氨酸的保护作用很可能与补充内皮型一氧化氮合酶（eNOS）产生的NO有关，但在本文的背景下无法完全解释。
