Essential role of pepsin in pathogenesis of acid reflux esophagitis in rats
Essential role of pepsin in pathogenesis of acid reflux esophagitis in rats
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DOI：
10.1007/s10620-006-3129-8
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发表时间：
2006-02-01
影响因子：
3.1
通讯作者：
Takeuchi, K
中科院分区：
文献类型：
--
作者：
Nagahama, K;Yamato, M;Takeuchi, K
胃蛋白酶是一种由胃酸激活的蛋白酶，是反流液的组成部分，但胃蛋白酶在反流性食管炎发病机制中的作用尚未得到充分研究。在本研究中，我们研究了胃蛋白酶抑制剂，胃蛋白酶的特异性抑制剂，对酸反流性食管炎的影响。通过结扎幽门和前胃3或4小时在大鼠中诱导酸反流性食管炎。结扎后灌胃给予胃酶抑素、ecabet Na（抗溃疡药物）和L-谷氨酰胺。胃蛋白酶抑制剂或依卡贝特钠，灌胃，显着防止食管病变，即使他们没有影响幽门结扎大鼠的基础酸分泌。胃蛋白酶抑制素在体内和体外显著抑制胃蛋白酶活性，而依卡贝特钠在体外抑制该活性。相比之下，L-谷氨酰胺灌胃给药以剂量依赖性方式加重了病变，但即使在L-谷氨酰胺存在下，胃酶抑素或ecabet Na联合给药也完全阻止了食管病变的发展。L-谷氨酰胺将胃内容物的pH值增加至约2.0，这是体外胃蛋白酶蛋白水解活性的最佳pH值。此外，胃内给予外源性胃蛋白酶加重了食管损伤的严重程度。这些结果表明，胃蛋白酶抑制剂是非常有效的酸反流性食管炎，不影响酸分泌。而L-谷氨酰胺通过改变管腔内pH至蛋白水解作用的最佳pH范围而增加胃蛋白酶活性，从而加重这些损伤。据推测，胃蛋白酶在酸反流性食管炎的发展中起主要致病作用。
Pepsin, a protease activated by gastric acid, is a component of the refluxate, yet the role of pepsin in the pathogenesis of reflux esophagitis has not been well studied. In the present study, we examined the effect of pepstatin, a specific inhibitor of pepsin, on acid reflux esophagitis. Acid reflux esophagitis was induced in rats by ligating both the pylorus and the forestomach for 3 or 4 hr. Pepstatin, ecabet Na (the anti-ulcer drug), and L-glutamine were administered intragastrically after the ligation. Pepstatin or ecabet Na, given intragastrically, significantly prevented esophageal lesions, even though they did not affect basal acid secretion in pylorus-ligated rats. Pepstatin significantly inhibited pepsin activity in vivo and in vitro, while ecabet Na inhibited this activity in vitro. By contrast, L-glutamine given intragastrically aggravated the lesions in a dose-dependent manner, but even in the presence of L-glutamine the development of esophageal lesions was totally prevented by coadministration of pepstatin or ecabet Na. L-Glutamine increased the pH of gastric contents to approximately 2.0, the optimal pH for the proteolytic activity of pepsin in vitro. In addition, intragastric administration of exogenous pepsin worsened the severity of esophageal damage. These results suggest that pepstatin is highly effective against acid reflux esophagitis, without influencing acid secretion. while L-glutamine aggravated these lesions by increasing the pepsin activity by shifting the intraluminal pH to the optimal pH range for proteolytic action. It is assumed that pepsin plays a major pathogenic role in the development of acid reflux esophagitis.