Molecular Changes Induced in Rat Liver by Hemorrhage and Effects of Melanocortin Treatment
Molecular Changes Induced in Rat Liver by Hemorrhage and Effects of Melanocortin Treatment
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DOI：
10.1097/aln.0b013e318246ea68
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发表时间：
2012-03-01
期刊：
影响因子：
8.8
通讯作者：
Guarini, Salvatore
中科院分区：
文献类型：
--
作者：
Lonati, Caterina;Sordi, Andrea;Guarini, Salvatore
背景：黑皮质素肽改善血液动力学参数，预防严重失血性休克死亡。在本研究中，我们确定了一个合成的黑皮质素1/4受体激动剂的分子变化，发生在大鼠肝脏hemorrhages.Methods的影响：控制容量出血在成年大鼠全身麻醉下逐步抽血，直到平均动脉压下降到40毫米汞柱。然后大鼠接受盐水或合成的黑皮质素1/4受体激动剂Butir-His-D-Phe-Arg-Trp-Sar-NH 2（Ro 27 -3225; n = 6-8/组）。在60分钟内进行血气分析。在肝脏样品中的基因表达测定在1或3小时，使用定量实时聚合酶链反应。结果：在1小时，在盐水处理的休克大鼠，有显着增加激活转录因子3（Atf 3），早期生长反应1（Egr 1），血红素加氧酶（decycling）1（Hmox 1），FBJ小鼠骨肉瘤病毒癌基因同源物（Fos），和Jun癌基因（Jun）。Ro 27 -3225阻止了这些变化（平均值+/- SEM：Atf 3 152.83 +/- 58.62 vs. 579.00 +/- 124.13，P = 0.002; Egr 1 13.21 +/- 1.28 vs. 26.63 +/- 1.02，P = 0.001; Hmox 1 3.28 +/- 0.31 vs. 166.54 +/- 35.03，P = 0.002; Fos 4.36 +/- 1.03 vs. 14.90 +/- 3.44，P < 0.001; Jun 6.62 +/- 1.93 vs. 15.07 +/- 2.09，P = 0.005）。在休克大鼠中，α 2-巨球蛋白（A2 m）、热休克蛋白1A（Hspa 1a）、促红细胞生成素（Epo）和白细胞介素-6（IL-6）在3 h时出现增加，并被Ro 27 -3225治疗所阻止（A2m 6.90 ± 0.82 vs. 36.73 ± 4.00，P < 0.001; Hspa1a 10.34 ± 3.28 vs. 25.72 ± 3.64，P = 0.001; Epo 0.49 ± 0.13 vs. 2.37 ± 0.73，P = 0.002; 116分别为1.05 +/- 0.15对1.88 +/- 0.23，P <0.01）。此外，在用Ro 27 -3225处理的休克大鼠中，在3小时时，紧密连接蛋白1显著增加，（Tjp 1; 27.30 +/- 2.43 vs.5.03 +/- 1.68，P < 0.001）和核受体亚家族4，A组，成员1（Nr4a1; 91.03 +/- 16.20 vs. 30.43 +/- 11.0，P = 0.01）。Ro 27 -3225治疗迅速恢复血压，hemogasanalysis参数，和lactate blood levels.Conclusions：黑皮质素治疗显着防止大部分的全身和肝脏的有害变化引起的出血。
Background: Melanocortin peptides improve hemodynamic parameters and prevent death during severe hemorrhagic shock. In the present research we determined influences of a synthetic melanocortin 1/4 receptor agonist on the molecular changes that occur in rat liver during hemorrhage.Methods: Controlled-volume hemorrhage was performed in adult rats under general anesthesia by a stepwise blood withdrawal until mean arterial pressure fell to 40 mmHg. Then rats received either saline or the synthetic melanocortin 1/4 receptor agonist Butir-His-D-Phe-Arg-Trp-Sar-NH2 (Ro27-3225; n = 6-8 per group). Hemogasanalysis was performed throughout a 60-min period. Gene expression in liver samples was determined at 1 or 3 h using quantitative real-time polymerase chain reaction.Results: At 1 h, in saline-treated shocked rats, there were significant increases in activating transcription factor 3 (Atf3), early growth response 1 (Egr1), heme oxygenase (decycling) 1 (Hmox1), FBJ murine osteosarcoma viral oncogene homolog (Fos), and jun oncogene (Jun). These changes were prevented by Ro27-3225 (mean +/- SEM: Atf3 152.83 +/- 58.62 vs. 579.00 +/- 124.13, P = 0.002; Egr1 13.21 +/- 1.28 vs. 26.63 +/- 1.02, P = 0.001; Hmox1 3.28 +/- 0.31 vs. 166.54 +/- 35.03, P = 0.002; Fos 4.36 +/- 1.03 vs. 14.90 +/- 3.44, P < 0.001; Jun 6.62 +/- 1.93 vs. 15.07 +/- 2.09, P = 0.005; respectively). Increases in alpha-2-macroglobulin (A2m), heat shock 70kD protein 1A (Hspa1a), erythropoietin (Epo), and interleukin-6 (Il6) occurred at 3 h in shocked rats and were prevented by Ro27-3225 treatment (A2m 6.90 +/- 0.82 vs. 36.73 +/- 4.00, P < 0.001; Hspa1a 10.34 +/- 3.28 vs. 25.72 +/- 3.64, P = 0.001; Epo 0.49 +/- 0.13 vs. 2.37 +/- 0.73, P = 0.002; Il6 1.05 +/- 0.15 vs. 1.88 +/- 0.23, P < 001; respectively). Further, at 3 h in shocked rats treated with Ro27-3225 there were significant increases in tight junction protein 1 (Tjp1; 27.30 +/- 2.43 vs. 5.03 +/- 1.68, P < 0.001) and nuclear receptor subfamily 4, group A, member 1 (Nr4a1; 91.03 +/- 16.20 vs. 30.43 +/- 11.0, P = 0.01) relative to sham animals. Treatment with Ro27-3225 rapidly restored blood pressure, hemogasanalysis parameters, and lactate blood levels.Conclusions: Melanocortin treatment significantly prevents most of the systemic and hepatic detrimental changes induced by hemorrhage.