Vish Michael G, Mangeshkar Prajakta, Piraino Giovanna, Denenberg Alvin, Hake Paul W, O'Connor Michael, Zingarelli Basilia
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, OH, USA.
Crit Care Med. 2007 May;35(5):1348-55. doi: 10.1097/01.CCM.0000260245.61343.B3.
Insulin connecting peptide (c-peptide) aids the folding of proinsulin and has been considered to have little biological activity. Recently, c-peptide has been shown to improve diabetic neuropathy and nephropathy as well as vascular inflammation. In vitro studies have reported that c-peptide may activate peroxisome proliferator-activated receptor-gamma, a nuclear transcription factor that plays a regulatory role in inflammation. This study was designed to investigate the biological effects of c-peptide during endotoxemia.
Prospective, randomized laboratory investigation that used an established murine model of endotoxic shock.
University hospital laboratory.
Mice were subjected to endotoxic shock by intraperitoneal administration of Escherichia coli lipopolysaccharide.
Mice received vehicle or c-peptide (70-140 nmol/kg) intraperitoneally at 3 hrs and 6 hrs after lipopolysaccharide. Mortality was monitored for 96 hrs. In a separate experiment, mice were killed at 4, 7, and 18 hrs after lipopolysaccharide administration. Lungs and plasma were collected for biochemical assays.
In vehicle-treated mice, endotoxic shock resulted in lung injury and was associated with a 41% survival rate and elevation in plasma tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-1, and keratinocyte-derived chemokine levels. Lung nuclear levels of phosphorylated extracellular signal-regulated kinases 1 and 2 were significantly increased in vehicle-treated mice. On the other hand, lung nuclear expression and DNA binding of proliferator-activated receptor-gamma were decreased in comparison to control animals. Treatment with c-peptide (140 nmol/kg) improved survival rate (68%) and reduced plasma levels of tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1, but it did not exert hypoglycemic effects. Treatment with c-peptide also up-regulated lung nuclear expression and DNA binding of proliferator-activated receptor-gamma and reduced phosphorylation of extracellular signal-regulated kinases 1 and 2 in comparison to vehicle-treated mice.
Our data show that c-peptide has beneficial effects in endotoxic shock, and this therapeutic effect is associated with activation of proliferator-activated receptor-gamma.
胰岛素连接肽（C肽）有助于胰岛素原的折叠，一直被认为几乎没有生物活性。最近，C肽已被证明可改善糖尿病性神经病变和肾病以及血管炎症。体外研究报告称，C肽可能激活过氧化物酶体增殖物激活受体γ，这是一种在炎症中起调节作用的核转录因子。本研究旨在探讨内毒素血症期间C肽的生物学效应。
前瞻性、随机实验室研究，使用已建立的内毒素休克小鼠模型。
大学医院实验室。
通过腹腔注射大肠杆菌脂多糖使小鼠遭受内毒素休克。
小鼠在脂多糖注射后3小时和6小时腹腔内接受溶剂或C肽（70 - 140 nmol/kg）。监测96小时的死亡率。在另一个实验中，在脂多糖给药后4小时、7小时和18小时处死小鼠。收集肺和血浆进行生化分析。
在接受溶剂处理的小鼠中，内毒素休克导致肺损伤，生存率为41%，血浆肿瘤坏死因子-α、巨噬细胞炎性蛋白-1α、单核细胞趋化蛋白-1和角质形成细胞衍生趋化因子水平升高。接受溶剂处理的小鼠肺细胞核中磷酸化细胞外信号调节激酶1和2的水平显著升高。另一方面，与对照动物相比，增殖物激活受体γ的肺细胞核表达和DNA结合减少。用C肽（140 nmol/kg）治疗可提高生存率（6至8%），并降低血浆肿瘤坏死因子-α、巨噬细胞炎性蛋白-1α和单核细胞趋化蛋白-1的水平，但未产生降血糖作用。与接受溶剂处理的小鼠相比，用C肽治疗还上调了增殖物激活受体γ的肺细胞核表达和DNA结合，并减少了细胞外信号调节激酶1和2的磷酸化。
我们的数据表明，C肽在内毒素休克中具有有益作用，且这种治疗作用与增殖物激活受体γ的激活有关。
