The modulation of hepatic injury and heat shock expression by inhibition of inducible nitric oxide synthase after hemorrhagic shock
The modulation of hepatic injury and heat shock expression by inhibition of inducible nitric oxide synthase after hemorrhagic shock
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DOI：
10.1097/00024382-200201000-00003
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发表时间：
2002-01-01
期刊：
影响因子：
3.1
通讯作者：
Harbrecht, BG
中科院分区：
文献类型：
--
作者：
Menezes, JM;Hierholzer, C;Harbrecht, BG
失血性休克时，一氧化氮(NO)在维持体内平衡和调节器官功能中的作用是复杂的。诱导型一氧化氮合酶(INOS)被认为在严重出血的病理生理后果中起关键作用。热休克蛋白(HSP)的表达因出血而增加，是肝脏缺血性损伤程度的标志。在炎症动物模型中，HSP的诱导对损伤具有保护作用，并受肝细胞内NO的调节。为探讨诱导型一氧化氮合酶在失血性休克大鼠肝损伤中的作用及其与热休克蛋白表达的关系，用L-N-6-(1-亚氨基乙基)赖氨酸(L-NIL)抑制一氧化氮合酶(INOS)，该药是诱导型一氧化氮合酶亚型的选择性抑制剂。代偿性休克结束后1h内分别输注50和150 mg/kg剂量。与生理盐水对照组(13.0+/-1.5IU/L，P<；0.005)相比，低剂量L-NIL(7.1+/-1.5IU/L)可显著降低失血大鼠血浆鸟氨酸氨基甲酰转移酶(OCT)的释放量(35.9+/-7.2IU/L，P<；0.05)，但复苏后OCT释放明显增加(与单纯休克相比，P<；0.05)。L无治疗高剂量组可增加出血后热休克蛋白的表达(热休克蛋白72和32)。结论：诱导型一氧化氮合酶产生过多的NO参与了休克肝损伤的发生。我们的数据提示，HSP的表达可能反映了出血后缺血损伤的程度。
The role of nitric oxide (NO) in maintaining homeostasis and regulating organ function during hemorrhagic shook is complex. The inducible NO synthase (iNOS) has been hypothesized to play a critical role in the pathophysiologic consequences of severe hemorrhage. Heat shock protein (HSP) expression is increased by hemorrhage and is a marker of the magnitude of ischemic injury in the liver. HSP induction is protective against injury in animal models of inflammation and is regulated by NO in hepatocytes. To clarify the role of iNOS in hepatic injury and its relationship to HSP expression in hemorrhagic shock, NOS was inhibited with L-N-6-(1-iminoethyl) lysine (L-NIL), which is reported to be a selective inhibitor of the inducible NOS isoform. Doses of 50 mug/kg or 150 mug/kg were infused over 1 h at the end of compensated shock. Plasma ornithine carbamoyltransferase (OCT), a specific marker of liver injury, was significantly reduced after hemorrhage with low-dose L-NIL (7.1 +/- 1.5 IU/L) compared to saline-treated control rats (13.0 +/- 1.5 IU/L, P< 0.005), while high-dose L-NIL significantly increased OCT release (35.9 +/- 7.2 IU/L, P< 0.05 versus shock alone) despite a greater MAP after resuscitation. HSP expression (HSP-72 and HSP-32) after hemorrhage was increased by L-NIL treatment at the highest dose. We conclude that excessive NO production from iNOS contributes to shock-induced hepatic injury. Our data suggest HSP expression may reflect the degree of ischemic injury after hemorrhage.