Pharmacological Studies on Gastric Mucosal Defense Mechanisms;Why doesn't the stomach digest itself?

本研究资助了以下研究：1）胃粘膜出血定量检测系统的建立：在清醒大鼠胃插管后，通过测定灌流液中漏出的红细胞数来判断胃出血的程度。束缚应激本身引起胃粘膜损伤，同时给予吲哚美辛或阿司匹林显著加重胃粘膜出血。2）药物作用：抗分泌药物、组胺H_2受体拮抗剂、抗胆碱能药、质子泵抑制剂等可有效地预防消炎痛引起的胃粘膜出血。而几种抗胃溃疡药物的抗分泌活性较弱，能增强胃粘膜的防御机制，对胃粘膜损伤也有保护作用。中枢抑制剂也能有效预防胃出血。日 ...更多信息 这些结果表明，不仅胃的攻击和防御机制，而且神经因素可能对胃粘膜的完整性有重要作用。3）药物的不良反应：抗肿瘤药物、抗生素、口服降糖药和作用于心血管系统的药物也会导致胃粘膜出血，表明胃粘膜对外源性化学物质具有抵抗性。4）组织蛋白酶活性的变化与溃疡形成有关，胃蛋白酶原是代表性的酸性蛋白酶之一，已被研究。然而，关于细胞内蛋白酶在胃肠道溃疡发病机制中的作用的报道很少。测定胃组织中的中性蛋白酶活性，特别是胃溃疡的发展。水浸束缚（应激）在应激暴露后2小时引起胃粘膜损伤或溃疡。组织酶活性在应激后15和30 min已被刺激，表明应激可在细胞内起作用以激活中性蛋白酶，这可能涉及细胞膜的消化以引起粘膜损伤。这一假说应在蛋白酶抑制剂方面进行更精确的研究。以下仍有待研究：1）与胃溃疡的发展和治疗阶段有关的高能相关磷化合物的组织水平2）粘膜抵抗力与胃功能的关系3）粘膜防御机制中的主要因素是什么，"防御"的控制或调节机制是什么？少

This grant supported to find the following evidence;1)Establishment of quantitative assay system of gastric mucosal bleeding:The numbers of the erythrocytes leaked into the perfusate was measured in the consciuos rat provided with gastric cannula in order to evaluate the degree of gastric hemorrhage. Restraint stress itself caused gastric mucosal damage and the concomitant administration of indomethacin or aspirin significantly exacerbated gastric mucosal bleeding. We concluded this model could be useful for the study of gastric mucosal defense mechanisms.2)Drug effects;Antisecretory drugs, histamine H_2-receptor antagonists,an anticholinergic,and proton pump inhibitors,effectively prevented the gastric mucosal bleeding caused by indomethacin. And several types of antiulcer drugs which have weak antisecretory activities and increase the mucosal defense mechanisms also protected the stomach from the mucosal lesions. Central depressants were also effective to prevent gastric bleeding. Th … More ese imply that not only gastric aggressive and defense mechanisms but also neural factors may have significant roles for gastric mucosal integrity.3)Adverse(unexpected) effects of the drugs:Antitumor drugs,antibiotics,oral hypoglycemic drugs and drugs acting on cardiovascular systems also resulted in gastric mucosal bleeding, suggesting that gastric mucosa is susceptive to exogenous chemicals.4)Changes in tissue protease activity with respect to ulcer formation; pepsinogen is one of the representative acidic protease and has been studied. However,there is few report on the role of intracellular proteases in relation to the pathogenesis of gastrointestinal ulcers. The neutral protease activity in the gastric tissue was determined with special reference to the development of gastric ulcers. Water-immersion restraint (stress) caused gastric mucosal lesions or ulcers 2 hours after the stress exposure. The tissue enzyme activity was already stimulated 15 and 30 min after the stress, suggesting that the stress may act intracellulanly to activate the neutral proteases and this may be involved in digestion of cellular membranes to cause mucosal damages. This hypothesis should be studied more precisely in terms of protease inhibitors.The followings are still open to be studied;1)Tissue levels of high-energy-related phosphor compounds with respect to the development and curative stage of gastric ulcers2)Relation between mucosal resistance and gastric function3)What's the major factor in mucosal defense mechanisms and how is the control or regulation mechanism of "the defense"? Less