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

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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.