c-Jun Terminal Kinase-2 Gene Deleted Mice Overexpress Hemeoxygenase-1 and Are Protected From Hepatic Ischemia Reperfusion Injury
c-Jun Terminal Kinase-2 Gene Deleted Mice Overexpress Hemeoxygenase-1 and Are Protected From Hepatic Ischemia Reperfusion Injury
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DOI：
10.1097/tp.0b013e3181ae3067
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发表时间：
2009-08-15
期刊：
影响因子：
6.2
通讯作者：
Wigmore, Stephen J.
中科院分区：
文献类型：
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作者：
Devey, Luke;Mohr, Elodie;Wigmore, Stephen J.
背景c-jun氨基末端激酶-2（jnk-2）的靶向缺失上调激活蛋白-1转录因子系统。我们假设这将导致血红素氧合酶-1（HO-1）的诱导，并赋予对肝脏缺血再灌注损伤的保护作用。野生型和jnk-2-/-动物在两种模型中经受肝缺血再灌注损伤：涉及定时Pringle操作的全肝缺血模型和涉及供应左肝叶的门脉蒂的选择性闭塞的部分肝缺血模型。每个模型的最佳损伤持续时间进行了校准。24小时后，处死动物，收集血液和组织用于丙氨酸转氨酶、组织学损伤评分和其他分析。在全部或部分肝缺血再灌注损伤之前，一些动物经受用铬中卟啉IX的HO-I抑制或用脂质体氯膦酸盐的枯否细胞耗竭。在用脂多糖刺激和测量肿瘤坏死因子-a的产生之前，从野生型和jnk-2-/-小鼠的造血祖细胞中培养骨髓来源的单核细胞。Jnk-2-/-动物受保护免于肝缺血再灌注损伤。HO-I表达和活性在jnk-2-/-动物中升高（2.2倍; P=0.006）。HO-I主要表达于枯否细胞。在jnk-2-/-动物中HO-I的抑制导致缺血保护的丧失。使用脂质体氯膦酸盐消耗枯否细胞导致野生型和jnk-2-/-动物肝脏HO-1表达丧失和更严重的损伤。体外培养的巨噬细胞的研究表明，减少肿瘤坏死因子-α分泌脂多糖刺激后，HO-1抑制后失去的效果。
Background. Targeted deletion of c-jun amino terminal kinase-2 (jnk-2) upregulates the activator protein-1 transcription factor system. We hypothesized that this would lead to induction of hemeoxygenase-1 (HO-1) and confer protection from hepatic ischemia reperfusion injury.Methods. Wild-type and jnk-2-/- animals were subjected to hepatic ischemia reperfusion insults in two models: a total hepatic ischemia model involving timed Pringle maneuver, and a partial hepatic ischemia model involving selective occlusion of the portal pedicle supplying the left hepatic lobe. Optimal durations of injury were calibrated for each model. After 24hr, animals were killed, and blood and tissues were collected for alanine aminotransferase, histologic injury scoring, and other analyses. Before total or partial hepatic ischemia reperfusion insults, some animals were subject to HO-I inhibition with chromium mesoporphyrin IX or Kupffer cell depletion with liposomal clodronate. Bone marrow-derived monocytes were grown from hemopoietic progenitors taken from wild-type and jnk-2-/- mice before stimulation with lipopolysaccharide and measurement of tumour necrosis factor-a production.Results. Jnk-2-/- animals were protected from hepatic ischemia reperfusion injury. HO-I expression and activity was elevated in jnk-2-/- animals (2.2-fold; P=0.006). Most HO-I was expressed in Kupffer cells. Inhibition of HO-I in jnk-2-/- animals led to the loss of protection from ischemia. Depletion of Kupffer cells using liposomal clodronate led to loss of hepatic HO-1 expression and much more severe injury in wild-type and jnk-2-/- animals. In vitro studies of cultured macrophages demonstrated reduced tumour necrosis factor-a secretion after lipopolysacharride stimulus, an effect lost after HO-1 inhibition.