Assimakopoulos Stelios F, Tsamandas Athanassios C, Alexandris Ilias H, Georgiou Christos, Vagianos Constantine E, Scopa Chrisoula D
Department of Internal Medicine, University Hospital of Patras, Patras 26504, Greece.
World J Gastrointest Pathophysiol. 2011 Dec 15;2(6):146-54. doi: 10.4291/wjgp.v2.i6.146.
To investigate the effect of the neuropeptides bombesin (BBS) and neurotensin (NT) on oval cell proliferation in partially hepatectomized rats not pretreated with a known hepatocyte inhibitor.
Seventy male Wistar rats were randomly divided into five groups: I = controls, II = sham operated, III = partial hepatectomy 70% (PHx), IV = PHx + BBS (30 μg/kg per day), V = PHx + NT (300 μg/kg per day). Forty eight hours after liver resection, portal endotoxin levels and hepatic glutathione redox state were determined. α-fetoprotein (AFP) mRNA (in situ hybridisation), cytokeratin-19 and Ki67 antigen expression (immunohistochemistry) and apoptosis (TUNEL) were evaluated on liver tissue samples. Cells with morphological features of oval cells that were cytokeratin-19 (+) and AFP mRNA (+) were scored in morphometric analysis and their proliferation was recorded. In addition, the proliferation and apoptotic rates of hepatocytes were determined.
In the control and sham operated groups, oval cells were significantly less compared to groups III, IV and V (P < 0.001). The neuropeptides BBS and NT significantly increased the proliferation of oval cells compared to group III (P < 0.001). In addition, BBS and NT induced a significant increase of hepatocyte proliferation (P < 0.001), whereas it decreased their apoptotic activity (P < 0.001) compared to group III. BBS and NT significantly decreased portal endotoxemia (P < 0.001) and increased the hepatic GSH: GSSG ratio (P < 0.05 and P < 0.001, respectively) compared to group III.
BBS and NT stimulated oval cell proliferation in a model of liver regeneration, without use of concomitant suppression of hepatocyte proliferation as oval cell activation stimuli, and improved the hepatocyte regenerative response. This peptides-induced combined stimulation of oval cell and hepatocyte proliferation might serve as a possible treatment modality for several liver diseases.
研究神经肽蛙皮素（BBS）和神经降压素（NT）对未用已知肝细胞抑制剂预处理的部分肝切除大鼠卵圆细胞增殖的影响。
70只雄性Wistar大鼠随机分为五组：Ⅰ组=对照组，Ⅱ组=假手术组，Ⅲ组=70%部分肝切除术（PHx）组，Ⅳ组=PHx + BBS（每天30μg/kg）组，Ⅴ组=PHx + NT（每天300μg/kg）组。肝切除术后48小时，测定门静脉内毒素水平和肝脏谷胱甘肽氧化还原状态。对肝组织样本进行甲胎蛋白（AFP）mRNA（原位杂交）、细胞角蛋白-19和Ki67抗原表达（免疫组织化学）以及凋亡（TUNEL）评估。在形态计量分析中对具有卵圆细胞形态特征且细胞角蛋白-19（+）和AFP mRNA（+）的细胞进行评分，并记录其增殖情况。此外，测定肝细胞的增殖和凋亡率。
与Ⅲ、Ⅳ和Ⅴ组相比，对照组和假手术组的卵圆细胞明显较少（P < 0.001）。与Ⅲ组相比，神经肽BBS和NT显著增加了卵圆细胞的增殖（P < 0.001）。此外，与Ⅲ组相比，BBS和NT诱导肝细胞增殖显著增加（P < 0.001），而其凋亡活性降低（P < 0.001）。与Ⅲ组相比，BBS和NT显著降低门静脉内毒素血症（P < 0.001），并提高肝脏谷胱甘肽（GSH）与氧化型谷胱甘肽（GSSG）的比值（分别为P < 0.05和P < 0.001）。
在肝再生模型中，BBS和NT刺激卵圆细胞增殖，无需作为卵圆细胞激活刺激同时抑制肝细胞增殖，并改善了肝细胞再生反应。这种肽诱导的卵圆细胞和肝细胞增殖的联合刺激可能作为几种肝脏疾病的一种可能治疗方式。
