Analysis of physiological roles of gastric acid in differentiation and proliferation of gastric mucosa and energy metabolism

本实验研究了组胺H_2受体基因敲除小鼠胃粘膜细胞分化和增殖的影响。我们已经产生了双基因敲除小鼠，其在各品系杂交后表达H2和胃泌素受体缺陷的表型。该双基因敲除方法为研究胃酸分泌机制及对胃粘膜分化和增殖的影响提供了实验依据。本研究以野生型小鼠为对照，观察了双基因敲除小鼠胃粘膜的组织学变化及糖脂代谢的改变。在双敲除表型中胃酸分泌减少。胃pH监测显示，与野生型相比，双敲表型恒定较高的值。双基因敲除小鼠胃粘膜细胞结构发生组织学改变。双敲除与野生型之间的存活时间没有差异。在相同的热量摄入下，双基因敲除小鼠的平均体重高于野生型小鼠。基因敲除小鼠的血糖和中性脂质水平也较高。与肌肉、肝脏和脂肪细胞肥大相关的PI3激酶活性在双基因敲除小鼠中略有增加。胃酸分泌减少和胃内pH升高是胃酸相关性疾病如反流性食管炎、胃溃疡和十二指肠溃疡的重要病理机制。我们的研究表明，胃内pH升高导致胃粘膜结构改变，不仅影响胃肠道的消化吸收，而且影响全身糖、脂代谢。

We have conducted the experiments to examine the effect of deficiency of histamine H2 receptor on differentiation and proliferation of gastric mucosa in histamine H2 receptor knock out mouse. We have generated a double knock out mouse which expresses phenotype of deficiencies both H2 and gastrin receptors after intercrossing of each line. This double knock out is useful for investigating the mechanism of gastric acid secretion and the influence on differentiation and proliferation of gastric mucosa. We investigated histological changes in gastric mucosa and alteration of lipid and glucose metabolism in double knock out mouse comparing with wild type mouse. Gastric acid secretion was decreased in double knock out phenotype. Gastric pH monitoring revealed constant higher values in double knock phenotype comparing with wild type. Histological change in cytoarchitecture of gastric mucosa was recognized in double knock out mice. There was no difference in survival time between double knock out and wild phenotype. Mean body weight in double knock out mice was higher than that of wild type mice under the same caloric intake. The levels of blood sugar and neutral lipids were also higher in knock out mice. The activity of PI3 kinase, which is related to hypertrophy of muscle, liver and fat calls, was slightly increased in double knock out mice. It is well known that the decrease of gastric acid secretion and the elevation of gastric pH play important roles in pathomechanism of gastric acid relater disorders, such as reflux esophagitis, pepsic ulcer and duodenal ulcer. Our present studies suggest that the elevation of gastric pH leads to changes of structure of gastric mucosa, which may affect not only digestion and absorption in GI tract, but glucose and lipids metabolism in whole bodies.