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

胃壁不断受到自身酸性物质以及细菌和摄入药物等危险物质的威胁。这些被称为COX抑制剂的药物，包括阿司匹林，被广泛用于治疗关节炎和其他炎症性疾病，并用于预防心脏病发作和中风。尽管COX抑制剂在这些情况下有价值，但在澳大利亚，由于胃溃疡副作用的并发症，COX抑制剂每年导致约5-10,000人住院。最近的一项进展是开发了一种名为COX-2抑制剂的亚类。在很短的时间内，其中一种药物已经成为澳大利亚最常见的处方药之一。COX-2抑制剂的优势是它们产生的胃溃疡要少得多。然而，它们只在最近没有溃疡病史的患者身上进行了测试。我们的初步实验，结合来自两个海外研究小组的一些相关信息，表明COX-2在胃部有用，并且在溃疡愈合时显著增加。我们的数据表明，阻断它会延迟实验性溃疡的愈合。该项目旨在了解COX-2在胃中的作用，并阐明当胃受损或受到威胁时抑制COX-2的效果。该项目还将寻找COX-2的S功能与我们发现的另一种被称为适应的保护过程之间的联系。当在特定条件下定期给大鼠或人类服用抗炎药时，几天后胃就会产生抵抗力，因此随后每一次给药造成的损害都会显著减少。在目前的NH和MRC拨款中，我们已经发现了一些负责这一点的机制，并计划探索这项工作提供的一些线索。该项目的意义在于，它有可能导致更安全地使用抗炎药或最终产生新的药物，以及它有可能为胃等器官的衬里如何保护自己提供新的知识。

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.