Aspirin in the 21st century
Rethinking the mechanism of aspirin
Dr Joan Clària – University of Barcelona, Barcelona, Spain
I presented data indicating that aspirin in addition to inhibiting prostaglandin formation, it triggers the formation of other lipid mediators that are also generated from arachidonic acids that are called 15-epi-lipoxins. The point is that this is a unique property of aspirin among all N sets because aspirin acetylated COX-2 so it blocks the formation of prostaglandins but, on the other side, it triggers the formation of these 15-epi-lipoxins which are derived from an intermediate that is formed from the COX, aspirin COX-2 acetylated enzyme, which is the 15R hit.
Can you tell us more about these novel eicosanoids?
The novelty of these eicosanoids, because they are eicosanoids they are generated from arachidonic acid, is that they carry anti-inflammatory properties; in opposite to prostaglandins which are inflammatory they have anti-inflammatory properties. So aspirin is unique because it blocks the formation of inflammatory prostaglandins but, on the other side, it triggers the formation of these anti-inflammatory mediators. They are really interesting because they not only are anti-inflammatory, they promote the resolution of inflammation. The resolution of inflammation is a part of the inflammatory response and is needed for the full recovery of the inflamed tissue. This is just a property that is specific for these 15-epi-lipoxins.
Can you overview the research you have been doing to determine how aspirin reduces inflammation?
In vitro it occurs at different concentrations of aspirin and in vivo, in experiments on animals, it also occurs at different concentrations of aspirin. There is a human study that included three different concentrations of aspirin and the concentration that was most efficient in the production of these anti-inflammatory mediators is the low dose, 81mg.
Is there a particular dose of aspirin that triggers these lipid mediators?
The problem is that aspirin has multifaceted effects so it’s pleiotropic so it can reduce thrombosis, it is anti-inflammatory, it can reduce cancer and other conditions so it’s important to know the full spectra or full mediators that are modified by aspirin. That’s why it’s so important to understand the mechanism.
Why is it important to understand more precisely how aspirin works?
They probably need to go into the clinical is that at present we are designing analogues that mimic these 15-epi-lipoxins because they have a very short half-life and are rapidly inactivated. So we are designing analogues that are resistant to inactivation to be used as a complimentary or as a unique treatment for the inflammatory conditions.
What are the clinical implications of your research?
That’s the important point of these new analogues, they will foster the resolution of the inflammatory risk zones, shortening the time that inflammation will resolve, and then this is very important because it’s unique for these mediators in opposite to the classical non-steroidal anti-inflammatory drugs. I would like also to add that when aspirin acetylated COX-2 it converts arachidonic acid into these 15-epi-lipoxins but this aspirin acetylated COX-2 also recognises other polyunsaturated fatty acids, especially those of omega-3. So now we are just uncovering that aspirin acetylated COX-2 can also generate epimers of omega-3 that are lipid mediators that share this anti-inflammatory and activities. So this is new ground that we are now expanding.
