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

我们通过实验研究了组胺H2受体缺失对组胺H2受体敲除小鼠胃粘膜分化和增殖的影响。我们已经产生了一个双敲除小鼠，表达H2和胃泌素受体的缺陷表型交叉后，每一个系。这种双敲除对研究胃酸分泌的机制以及对胃粘膜分化和增殖的影响具有重要意义。研究了双敲除小鼠与野生型小鼠胃粘膜的组织学变化及脂糖代谢的变化。双敲除表型胃酸分泌减少。胃pH监测显示，与野生型相比，双敲表型的值不断升高。双敲除小鼠胃粘膜细胞结构发生组织学改变。双敲除型和野生型在存活时间上没有差异。在相同热量摄入下，双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的水平也更高。与肌肉、肝脏和脂肪细胞肥大有关的PI3激酶活性在双敲除小鼠中略有增加。众所周知，胃酸分泌减少和胃pH升高在胃酸相关疾病如反流性食管炎、消化性溃疡和十二指肠溃疡的发病机制中起重要作用。我们目前的研究表明，胃pH升高引起胃粘膜结构的改变，不仅影响胃肠道的消化吸收，而且影响全身的葡萄糖和脂质代谢。

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.