Laura Menke PhD candidate, Queen Mary University of London
Inflammation vs. Resolution
Atherothrombosis is the leading cause of death worldwide and can be linked to the formation of blood clots in the vascular system. Depending on the location of clot formation, atherothrombosis can stimulate a variety of disease pathologies such as stroke, heart infarct and even leg ischemia, which makes research regarding prevention and treatment of this disease so important. Epidemiological studies indicate that in our society with increased age and enhanced obesity and diabetes prevalence, the risk of vascular diseases will further increase and reach epidemic proportions in the coming decades 1.
Inflammation: A Hallmark of Atherosclerotic Disease
Inflammation is a recognized pathologic hallmark in the development of atherosclerotic diseases by contributing to endothelial dysfunction and plaque development 2. As seen in many chronic inflammatory diseases, failure to instigate inflammatory resolution leads to an excessive inflammatory response followed by disease progression3.
Failure to decrease inflammation and return to homeostasis has gained widespread attention over the last several years, resulting in enhanced research interest in the mechanisms and cellular processes regulating vascular inflammation and resolution.
In the past, it was thought that the passive dilution of inflammatory mediators in the tissue leads to the resolution of inflammation. However, significant research revealed that the resolution of inflammation is an active process that is mediated by a switch of the cellular inflammatory to resolving programme 4. Key mediators of inflammation are eicosanoids, endogenous, biological active mediators, that play a crucial role in regulating cellular functions. Changes in environmental stimuli directly influence the eicosanoid production and can be identified as an abnormal profile in the plasma of patients5,6.
Dietary changes to promote Resolution
That dietary changes can help to boost endogenous protective mechanisms has first been suggested after observing that Eskimos in Alaska, who on average consume 20 times as much omega-3 fatty acids via fish than people on a western diet, have a reduced risk of obesity and heart diseases 7. On the other hand, omega-6 fatty acids, as found in red meat or some plant oils, have generally been linked to an increase in disease risk8.
Interestingly, several clinical cohort studies of dietary supplementation with Omega-6 fatty acids, such as Linoleic Acid, display contradictory results on the impact on cardiovascular diseases and show that the response to intake highly depends fatty acid type, concentration, duration and timing of exposure 9. Linoleic acid can be directly metabolized to a variety of other fatty acids of the omega-6 family with different functionalities. The conversion rate and type of product highly depends on substrate availability and enzyme activity and selectivity. Enhanced research into the effects of fatty acid exposure on immune cells has clarified that this response is due to the activation of alternative metabolic pathway that stimulate the production of both anti- and pro-resolving mediators5.
Platelets and their role in inflammation
Even though platelets are predominantly linked to haemostasis, they have recently been recognized in playing an essential role in the innate and adaptive immune responses by directly interacting with immune cells. Following activation, platelets undergo a shape change and display a variety of receptors on their surface that allows them to associate in aggregates (platelet-platelet aggregates, platelet-leucocyte aggregates). Adhesion to leucocytes has shown to induce cell-specific signalling pathways essential for inflammation. Next to direct interaction, platelets also release an array of pro-inflammatory eicosanoid via metabolism of arachidonic acid that is release from the cell membrane 10.
The most important eicosanoid in platelet activation is thromboxane A2, a key player of inflammation. Current treatments of vascular diseases involve the application of anti-platelet therapies with Aspirin, that blocks the enzyme cyclooxygenase 1 (Cox1), responsible for thromboxane A2 production.
Even though Aspirin is effective in a lot of patients, some people still develop cardiovascular pathologies as a result of aspirin resistance and alternative pathways 11. In conclusion, inhibiting platelet function by additional approaches could be beneficial for clinical application.
Inhibiting platelet function might improve endogenous tissue protection
Linoleic acid is the most abundant omega-6 fatty acid in the diet and it has been recently displayed that it has an inhibitory effect on platelet aggregation after direct exposure . Additionally, recent studies indicated that the direct product of Linoleic acid, dihomo-γ-linoleic acid (DGLA) inhibits platelet function both directly12 and when supplied as dietary supplement13. This is specifically fascinating as arachidonic acid, a downstream product from DGLA, activates platelets, resulting in the formation of aggregates and increased thrombotic risk. In conclusion, it is suggested that the anti-thrombotic effect of DGLA is due to alternative metabolic pathways that produce novel, protective products such as PGE1 and 12-HETrE. Interestingly, DGLA is oxidized by the same enzymes as arachidonic acid ,Cox-1 and 12-LOX, and even though those enzymes process both substrates at the same rate, it was shown that increase of DGLA results in the reduction of AA-derived products and increase of anti-thrombotic products from DGLA14,15 (Figure 1).
Figure 1: Conversion pathway of Ï‰-6 fatty acids in platelets and their function. Yellow: anti-aggregatory metabolite, blue: pro-aggregatory metabolite. Figure adapted from Wang 2012 et al.
Due to the promising results, latest advances have now been focusing on the direct application of those products, such as PGE1, for a more targeted approach. For example, application of a high-dose PGE1 drip infusion in addition to stent placement for arteriosclerotic occlusive lesion treatment significantly improved the clinical outcome by decreasing platelet deposition and the production of microthrombin in cardiovascular disease patients 16. Also, intravenous administration of PGE1 via nanoparticles secured targeted and sustained delivery to the occlusion side and improved the walking distance in a rat model of intermittent claudication 17.
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- Georgiadis AL, Cordina SM, Vazquez G, et al. Aspirin treatment failure and the risk of recurrent stroke and death among patients with ischemic stroke. J Stroke Cerebrovasc Dis. 2013;22(2):100-106. doi:10.1016/j.jstrokecerebrovasdis.2011.06.017.
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- Ikushima I, Hirai T, Ishii A, Yamashita Y. Combined stent placement and high dose PGE1 drip infusion for chronic occlusion of the superficial femoral artery as a modality to salvage chronic critical limb ischemia. Eur J Radiol. 2008;66(1):95-99. doi:10.1016/j.ejrad.2007.04.025.
- Ishihara T, Yamashita Y, Takasaki N, et al. Prostaglandin E1-containing nanoparticles improve walking activity in an experimental rat model of intermittent claudication. J Pharm Pharmacol. 2013;65(8):1187-1194. doi:10.1111/jphp.12080.