Fiorucci S, Bufalari A, Distrutti E, Bufalari A, Lanfrancone L, Servoli A, Sarpi L, Federici B, Bartoli A, Morelli A, Moggi L
Gastroenterology and Digestive Endoscopy Clinic, Dept. of General and Vascular Surgery, Università degli Studi di Perugia, Italy.
Scand J Gastroenterol. 1998 Dec;33(12):1310-20. doi: 10.1080/00365529850172412.
In several animal species the pancreas has the capacity to partially regenerate in a self regulating process. A complex network of growth factors modulates this process. There is evidence that bombesin stimulates pancreatic regeneration in rodents. Whether bombesin stimulates pancreas regrowth in large mammals is unknown. Shc proteins, the target of tyrosine kinase-coupled receptors, activate p42 and p44 mitogen-activated protein (MAP) kinase and induce the transcriptional upregulation of genes involved in cell proliferation. The aims of our study were to determine whether bombesin stimulates pancreatic growth in large mammals and whether this event requires Shc-MAP kinase pathway upregulation.
Three groups of pigs were submitted to sham operation (group 1); to subtotal (70%) distal pancreatectomy (group 2), and to subtotal pancreatectomy followed by bombesin (5 mg three times daily) for 4 weeks (group 3). After a 4-week follow-up a second laparotomy was performed, and the residual pancreas removed. p46Shc, p52Shc and p66Shc, Grb2, and p42/p44 MAP kinase expression and phosphorylation were measured either in freshly isolated pancreatic acinar cells or whole pancreatic extracts.
In vivo bombesin administration resulted in: 1) approximately 100% growth of pancreatic duodenal lobe; 2) rapid recovery from exocrine pancreatic failure; and 3) a threefold increase in the rate of pancreatic acinar cell proliferation. Incubating freshly isolated pancreatic acinar cells with bombesin resulted in time- and concentration-dependent stimulation of p46Shc/p52Shc phosphorylation, Shc-Grb2 complex formation, and p42/p44 MAP kinase activation. In vivo bombesin administration significantly upregulated p46Shc/p52Shc and MAP kinase expression and/or activity in whole pancreatic extracts.
In vivo chronic bombesin administration stimulates pancreatic regeneration after pancreatectomy in large mammals. Bombesin-stimulated pancreatic growth is associated with upregulation of the Shc-Grb2-SOS-Ras-MAP kinase pathway.
在一些动物物种中，胰腺有能力在自我调节过程中进行部分再生。一个复杂的生长因子网络调节这一过程。有证据表明蛙皮素可刺激啮齿动物的胰腺再生。蛙皮素是否能刺激大型哺乳动物的胰腺再生尚不清楚。Shc蛋白是酪氨酸激酶偶联受体的靶点，可激活p42和p44丝裂原活化蛋白（MAP）激酶，并诱导参与细胞增殖的基因转录上调。我们研究的目的是确定蛙皮素是否能刺激大型哺乳动物的胰腺生长，以及这一过程是否需要Shc-MAP激酶途径上调。
将三组猪分别进行假手术（第1组）；次全（70%）远端胰腺切除术（第2组），以及次全胰腺切除术后给予蛙皮素（5mg，每日3次），持续4周（第3组）。4周随访后进行第二次剖腹手术，切除残余胰腺。在新鲜分离的胰腺腺泡细胞或全胰腺提取物中检测p46Shc、p52Shc和p66Shc、Grb2以及p42/p44 MAP激酶的表达和磷酸化。
体内给予蛙皮素导致：1）胰腺十二指肠叶生长约100%；2）从外分泌性胰腺功能衰竭中快速恢复；3）胰腺腺泡细胞增殖率增加三倍。用蛙皮素孵育新鲜分离的胰腺腺泡细胞导致p46Shc/p52Shc磷酸化、Shc-Grb2复合物形成以及p42/p44 MAP激酶激活的时间和浓度依赖性刺激。体内给予蛙皮素显著上调全胰腺提取物中p46Shc/p52Shc和MAP激酶的表达和/或活性。
体内长期给予蛙皮素可刺激大型哺乳动物胰腺切除术后的胰腺再生。蛙皮素刺激的胰腺生长与Shc-Grb2-SOS-Ras-MAP激酶途径上调有关。
