Bombesin-induced pancreatic regeneration in pigs is mediated by p46(Shc)/p52(Shc) and p42/p44 mitogen-activated protein kinase upregulation

Background: In several animal species the pancreas has the capacity to part ially 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 re growth in large mammals is unknown. Shc proteins, the target of tyrosine ki nase-coupled receptors, activate p42 and p44 mitogen-activated protein (MAP ) kinase and induce the transcriptional upregulation of genes involved in c ell proliferation. The aims of our study were to determine whether bombesin stimulates pancreatic growth in large mammals and whether this event requi res She-MAP kinase pathway upregulation. Methods: Three groups of pigs were submitted to sham operation (group 1); to subtotal (70%) distal pancreatec tomy (group 2), and to subtotal pancreatectomy followed by bombesin (5 mg t hree times daily) for 4 weeks (group 3). After a 4-week follow-up a second laparotomy was performed, and the residual pancreas removed. p46(Shc), p52( Shc) and p66(Shc), Grb2, and p42/p44 MAP kinase expression and phosphorylat ion were measured either in freshly isolated pancreatic acinar cells or who le pancreatic extracts. Results: In vivo bombesin administration resulted i n: 1) similar to 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 pancre atic acinar cells with bombesin resulted in time- and concentration-depende nt stimulation of p46(Shc)/p52(Shc) phosphorylation, Shc-Grb2 complex forma tion, and p42/p44 MAP kinase activation. In vivo bombesin administration si gnificantly upregulated p46(Shc)/p52(Shc) and MAP kinase expression and/or activity in whole pancreatic :extracts. Conclusions: In vivo chronic bombes in administration stimulates pancreatic regeneration after pancreatectomy i n large mammals. Bombesin-stimulated pancreatic growth is associated with u pregulation of the Shc-Grb2-SOS-Ras-MAP kinase pathway.