Interaction between epidermal growth factor and gastrin on DNA synthesis of the gastrointestinal mucosa in rats.

Interaction between epidermal growth factor (EGF) and gastrin on DNA synthesis of the rat gastrointestinal tract was examined. Fasted male rats were divided into four groups and injected with 10 μg/kg human EGF, 300 μg/kg pentagastrin, human EGF plus pentagastrin and saline (control), respectively. The animals were sacrificed 8 or 16 hr thereafter and the incorporation of [H]thymidine into the gastrointestinal mucosa was measured. Human EGF increased DNA synthesis of the fundus, antrum and cecum, while pentagastrin stimulated that of the fundus, duodenum, ileum and proximal colon. Synchronous administration of these peptides also stimulated DNA synthesis of the fundus, antrum and cecum. However, in the ileum and proximal colon, DNA synthesis stimulated by pentagastrin was suppressed by the administration of both agents synchronously. These data suggest that these growth factors regulate the growth of gastrointestinal tract with complex interactions. J(ey words: Human epidermal growth factor, DNA synthesis, Gastrointestinal mucosa Mouse epidermal growth factor (mouse EGF), which was first isolated from male mouse submandibular glands>, is a polypeptide containing 53 amino acids and stimulates the growth of many tissues in vitro and in vivo•••>. Human {3urogastrone, a potent inhibitor of gastric acid secretion>, was subsequently isolated from human urine and is probably identical to human EGF•>. In the gastrointestinal mucosa, EGF stimulation of DNA synthesis has been reported with some contradictory results••••7). Some investigators have reported that mouse EGF is a trophic substance for only oxyntic gland mucosa of the stomach and the duodenum in rats•>. But in the mouse system, trophic effect of mouse EGF has been observed in most part of gastrointestinal tract•>. Al-Nafussi and Wright> had also found that the response of gastrointestinal mucosa to EGF differed in rats and mice. The differential growth response of the gastrointestinal mucosa to exogenous EGF is considered to be due to the specificitity of animal species used in the experiments. On the other hand, Gastrin, a classic and wellestablished gastrointestinal hormone, shows a trophic influence on the gastrointestinal mucosa and stimulates gastric acid secretion and pancreatic enzyme secretion•>. We have also demonstrated that gastrin promotes the growth of a human gastric cancer cell line as well as a xenotransplantable human gastric carcinoma in nude mice•>. Johnson and Guthrie> had examined the effects of EGF and gastrin individually on the growth of rat oxyntic glands and hypothsized that acid secretion and mitogenesis are the results of two separate mechanism. However, the effect of synchronous administration of EGF and gastrin or the interaction between EGF and gastrin on DNA synthesis of the gastrointestinal mucosa has not been reported. The present study was made to investigate the trophic effect of human EGF on the rat gastrointestinal mucosa. Moreover, the interaction between human EGF and gastrin on DNA synthesis of gastrointestinal mucosa was examined. MATERIALS AND METHODS Animals and Treatments Six-week-old male Wistar strain rats (JCL Wistar rat, Japan Clea Co., Osaka, Japan) weighing 120-140 g were employed in the present study. Forty rats were randomly divided into four equal groups and fasted for 24 h. During this time they had free access to water. The first group received lOμg/kg body weight human EGF intravenously through the tail vein. Highly purified hEGF which was prepared from a genetic-engineered E. coli host and had full bioactivity was kindly supplied by Wakunaga Pharm. Co., Hiroshima, Japan>. It had been confirmed that 2-25 μg/kg body weight of human EGF showed a maximal trophic influence on rat various organs). The second group received pentagastrin (300 μg/kg body weight, Sumitomo