Department of Trauma Surgery, J. W. Goethe University, Frankfurt, Germany.
Shock. 2009 Nov;32(5):509-16. doi: 10.1097/SHK.0b013e3181a2530d.
Inhibition of c-Jun N-terminal kinase (JNK) by a cell-penetrating, protease-resistant JNK peptide (D-JNKI-1) before hemorrhage and resuscitation (H/R) ameliorated the H/R-induced hepatic injury and blunted the proinflammatory changes. Here we tested the hypothesis if JNK inhibition at a later time point-after hemorrhagic shock but before the onset of resuscitation-in a rat model of H/R also confers protection. Twenty-four male Sprague-Dawley rats (250 - 350 g) were randomly divided into 4 groups: 2 groups of shock animals were hemorrhaged to a MAP of 32 to 37 mmHg for 60 min and randomly received either D-JNKI-1 (11 mg/kg i.p.) or sterile saline as vehicle immediately before the onset of resuscitation. Two groups of sham-operated animals underwent surgical procedures without H/R and were either D-JNKI-1 or vehicle treated. Rats were killed 2 h later. Serum activity of alanine aminotransferase and serum lactate dehydrogenase after H/R increased 3.5-fold in vehicle-treated rats as compared with D-JNKI-1-treated rats. Histopathological analysis revealed that hepatic necrosis and apoptosis (hematoxylin-eosin, TUNEL, and M30, respectively) were significantly inhibited in D-JNKI-1-treated rats after H/R. Hepatic oxidative (4-hydroxynonenal) and nitrosative (3-nitrotyrosine) stress as well as markers of inflammation (hepatic and serum IL-6 levels and hepatic infiltration with polymorphonuclear leukocytes) were also reduced in D-JNKI-1-treated rats. LPS-stimulated TNF-alpha release from whole blood from hemorrhaged and resuscitated animals was higher in vehicle-treated rats as compared with D-JNKI-1-treated rats. c-Jun N-terminal kinase inhibition after hemorrhage before resuscitation resulted in a reduced activation of c-Jun. Taken together, these results indicate that D-JNKI-1 application after hemorrhagic shock before resuscitation blunts hepatic damage and proinflammatory changes during resuscitation. Hence, JNK inhibition is even protective when initiated after blood loss before resuscitation. These experimental results indicate that the JNK pathway may be a possible treatment option for the harmful consequences of H/R.
在出血和复苏（H/R）之前，通过穿透细胞的、抗蛋白酶的 JNK 肽（D-JNKI-1）抑制 c-Jun N-末端激酶（JNK）可改善 H/R 引起的肝损伤并减轻促炎变化。在这里，我们测试了这样一个假设，如果在出血性休克后但在复苏开始之前的一个时间点抑制 JNK，是否也会在 H/R 的大鼠模型中提供保护。24 只雄性 Sprague-Dawley 大鼠（250-350g）被随机分为 4 组：2 组休克动物的 MAP 降至 32 至 37mmHg 并维持 60min，然后随机在复苏开始前接受 D-JNKI-1（11mg/kg 腹腔注射）或无菌盐水作为载体。2 组假手术动物接受手术但不进行 H/R，并用 D-JNKI-1 或载体处理。2h 后处死大鼠。与 D-JNKI-1 处理的大鼠相比，H/R 后接受载体治疗的大鼠血清丙氨酸氨基转移酶和血清乳酸脱氢酶的活性增加了 3.5 倍。组织病理学分析显示，H/R 后 D-JNKI-1 处理的大鼠肝坏死和凋亡（苏木精-伊红、TUNEL 和 M30）明显减少。D-JNKI-1 处理的大鼠肝氧化（4-羟壬烯醛）和硝化（3-硝基酪氨酸）应激以及炎症标志物（肝和血清 IL-6 水平以及肝内多形核白细胞浸润）也减少。与 D-JNKI-1 处理的大鼠相比，从出血和复苏动物的全血中刺激 LPS 释放的 TNF-α在载体处理的大鼠中更高。与 D-JNKI-1 处理的大鼠相比，出血前复苏时抑制 c-Jun N-末端激酶可导致 c-Jun 的激活减少。综上所述，这些结果表明，出血性休克后复苏前给予 D-JNKI-1 可减轻复苏期间的肝损伤和促炎变化。因此，在开始复苏前失血时抑制 JNK 也是有保护作用的。这些实验结果表明，JNK 途径可能是治疗 H/R 有害后果的一种可能选择。
