Mechanisms of repair and adaptation in the gastric mucosa: roles of COX-2 and growth factors

胃粘膜不断受到自身胃酸以及细菌和摄入的药物等危害的威胁。包括阿司匹林在内的COX抑制剂被广泛用于治疗关节炎和其他炎症性疾病，以及预防心脏病发作和中风。尽管COX抑制剂在这些疾病中有价值，但由于胃溃疡副作用引起的并发症，澳大利亚每年约有5-10,000例COX抑制剂入院。最近的一项进展是开发了一种称为COX-2抑制剂的亚类。在很短的时间内，其中一种已经成为澳大利亚最常用的处方药之一。COX-2抑制剂的优点是它们产生的胃溃疡少得多。然而，它们只在近期没有溃疡史的患者中进行了测试。我们的初步实验，以及来自两个海外小组的一些相关信息，表明COX-2在胃中是有用的，并且在愈合的溃疡周围显着增加。我们的数据表明，阻断它会延迟实验性溃疡的愈合。本项目旨在了解COX-2在胃中的作用，阐明在胃受到损伤或威胁时抑制COX-2的作用。该项目还将寻找COX-2功能与我们发现的另一种称为“适应”的保护过程之间的联系。在一定条件下，定期给大鼠或人服用消炎药，胃在几天后就会产生耐药性，因此随后每次给药所造成的损害就会明显减少。在目前的NH和MRC拨款期间，我们已经发现了一些导致这种情况的机制，并计划探索这项工作所带来的一些线索。这个项目的重要意义在于，它有可能使抗炎药物的使用更安全，或者最终开发出新的药物，而且它有可能提供有关胃等器官内膜如何自我保护的新知识。

The stomach lining is continually threatened by its own acid and by hazards such as bacteria and ingested drugs. The drugs called COX inhibitors, which include aspirin, are widely used for treating arthritis and other inflammatory diseases and for preventing heart attacks and strokes. Despite their value in these conditions, COX inhibitors are responsible for about 5-10,000 hospital admissions annually in Australia due to complications from the side effect of stomach ulcers. A recent advance has been the development of a sub-class called COX-2 inhibitors. In a very short time, one of these has become among the most prescribed drugs in Australia. The advantage of the COX-2 inhibitors is that they produce many less stomach ulcers. However, they have only been tested in patients who have not had a recent history of ulcer. Our preliminary experiments, together with some related information from two overseas groups, suggests that COX-2 is useful in the stomach, and is markedly increased around a healing ulcer. Our data suggest that blocking it delays the healing of experimental ulcers. This project aims to understand the roles of COX-2 in the stomach, and to clarify the effects of inhibiting it when the stomach is damaged or threatened. The project will also look for links between COX-2's functions and another protective process we have discovered called 'adaptation'. When anti-inflammatory drugs are given regularly to rats or humans under certain conditions, the stomach develops resistance after a few days so that the damage caused by each subsequent dose is markedly reduced. We have uncovered a number of mechanisms responsible for this during a current NH and MRC grant, and plan to explore some of the leads this work has given. The SIGNIFICANCE of the project is its potential to lead to safer use of anti-inflammatory drugs or eventually to new agents, and its potential to give new knowledge about how the lining of organs such as the stomach protects itself.