Silent Inflammation – Influence of the marine omega-3 fatty acids EPA/DHA

If this silent inflammation persists over a longer period of time, it container predispose the affected group of people to the occurrence of a number of chronic inflammatory conditions. This container have a negative impact on general health status and personal well-being and also generally increase the risk of health-threatening events occurring. Subliminal inflammation is characterized by a permanent increase in inflammatory mediators. These pro-inflammatory biomarkers container have continuous, functionally impairing effects on various body cells and tissues before this becomes noticeable through clinical symptoms, which then make the presence of a chronic, disease-causing event obvious. Some of these biomarkers circulate in the blood and are therefore easily accessible to determination, which container provide valuable information about pathological processes taking place in the body. They container also serve as an indicator of the success of a dietary or therapeutic intervention.

The inflammatory genesis of certain chronic diseases has long been known. These include rheumatoid arthritis, inflammatory bowel diseases (eg ulcerative colitis and Crohn's disease), psoriasis, certain types of containercer^[1] and asthma, to name just a few examples.

Numerous clinical studies have now also shown that subthreshold inflammatory conditions are a serious risk factor for the development of atherosclerosis and also underlie many other cardiovascular risk factors, including the metabolic syndrome in overweight and obesity, which precedes type 2 diabetes.^{[2], [3]}It is now also assumed that inflammatory mediators and the inflammatory response to them play an important role in silent cerebral infarctions and clinically manifest stroke events and are also involved in stress-induced depression and in the pathogenesis of Alzheimer's disease.^{[4], [5], [6], [7]}

Persistent subthreshold inflammatory states in the body are triggered by a whole range of chemical mediators.

The movement of certain white blood cells, monocytes and macrophages, to the inflamed sites is facilitated by so-called adhesion molecules (including ICAM-1 (Intercellular Adhesion Molecule 1) and VCAM-1 (Vascular Cell Adhesion Molecule 1). These cells then produce pro-inflammatory mediators known as cytokines (including various interleukins such as interleukin-6 and tumor necrosis factor TNF-α). In addition, these cells produce substantial amounts of a certain eicosanoid, PGE2 (prostaglandin E2), and additionally PGF2α (prostaglandin F2α). PGE2 triggers a variety of pro-inflammatory effects, including increased production of cytokines.^[8]

It is very important to note that the omega-6 fatty acid arachidonic acid (AA) is the precursor (substrate) for the enzymatic synthesis of the eicosanoids PGE2 and PGF2α.

Unfavorable dietary habits, such as excessive intake of omega-6 fatty acids and low intake of marine omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are responsible for the increased content of arachidonic acid (AA) in the cell membranes of the white blood cells monocytes and macrophages. The high concentration of arachidonic acid (AA) in the cells is directly causally related to the subsequent increased formation of the inflammatory mediator PGE2 and other pro-inflammatory mediators. This status is already found in large parts of the population in America, Europe and Australia, with the further spread of the "western" omega-6 fatty acid-heavy diet increasingly extending these risk factors to other populations, e.g. in Asia.^[9]

Neutrophil granulocytes (a fraction of white blood cells) subsequently play an important role in this inflammatory process because they produce another very effective pro-inflammatory eicosanoid, leukotriene B4 (LTB4). Arachidonic acid (AA) is in turn the precursor of the enzyme-controlled synthesis of LTB4.

Other representatives of these leukotrienes from the “series of 4” are produced in other cells such as mast cells and basophils and eosinophils.

A higher intake of EPA and DHA with the diet, either in the form of fish or in the form of marine omega-3 fatty acid supplements, leads to lower concentrations of arachidonic acid (AA), which is then ultimately missing for the synthesis of LTB4 in the neutrophil granulocytes. This then leads to a reduction in the formation of the pro-inflammatory eicosanoid LTB4.

It is worth mentioning in this context that there is now a new class of drugs, so-called leukotriene receptor antagonists, which bind to the leukotriene receptors and thereby block the effect of leukotrienes in the inflammatory process. They are currently being used successfully in asthma prophylaxis and have an anti-inflammatory effect by inhibiting the effect of the leukotrienes released by inflammatory cells that have migrated into the bronchi.^[10]

The above-mentioned increase in chemical inflammatory mediators in silent inflammation is partly responsible for the genesis of a variety of inflammation-related pathological processes and resulting diseases.

Epidemiological studies have shown the association between the intake of Omega-3 fatty acids, especially of EPA and DHA, through fish consumption or fish oil consumption and inflammatory biomarkers.

A clinical study of 727 nurses as part of the longitudinal Nurses' Health Study (NHS) conducted by the Harvard School of Public Health showed that higher intake of marine omega-3 fatty acids correlates with lower levels of selected biomarkers (including interleukin-6), which indicate lower levels of inflammation.^[11] Increasingly higher combined intake of EPA/DHA was correlated with significontainertly lower circulating levels of ICAM-1 and VCAM-1: comparing the quintile of the study population with an intake (median) of 450 mg EPA/DHA per day (top 20%) with the quintile of the lowest intake of 70 mg EPA/DHA per day (bottom 20%). It should be noted that the average intake of EPA/DHA in North America is generally at a very low level, between 130-150 mg EPA/DHA (combined) per day, which is due to the low intake of fish and seafood.

A joint study was conducted by Italian and Americontainer researchers on a large number of subjects (1123 people aged 20-98 years). The association between blood plasma levels of polyunsaturated fatty acids (biomarkers of dietary intake) and circulating pro-inflammatory mediators was investigated.^[12]

Interestingly, the segment of study participants in the highest quartile (top 25%, in terms of highest EPA or DHA plasma concentrations) had significontainertly lower concentrations of inflammation-mediating cytokines, measured as interleukin-6 or tumor necrosis factor TNF-α.

The authors conclude that the low intake of omega-3 fatty acids observed in older individuals reinforces the age-related trend toward a pro-inflammatory status.

Some intervention studies (“before-after studies”) have also shown that supplementation with EPA/DHA container reduce the concentrations of pro-inflammatory biomarkers. This is naturally much more difficult than in the epidemiological studies described above, since the study period in intervention studies is usually relatively short.

For example, an intervention study in postmenopausal women undergoing hormone replacement therapy showed that a five-week administration of 1100-2200 mg EPA/DHA (combined) per day reduced circulating concentrations of interleukin-6.^[13] Rupp et al.^[14] have suggested higher daily intakes of 2000 – 4000 mg EPA/DHA (combined) per day for a reduction in pro-inflammatory eicosanoids and cytokines.

Future study designs should therefore include a much longer study period than previous studies and it would also be of great interest to establish a dose-effect relationship by groups with intake of different amounts of EPA/DHA.

In most human studies that have demonstrated a positive effect against chronic inflammatory conditions, different mixed concentrations of EPA and DHA were used. Both omega-3 fatty acids container help reduce pro-inflammatory factors via slightly different but complementary mechanisms.

In animal studies in which sufficient amounts of EPA/DHA (combined) were administered to reduce pro-inflammatory mediators, different concentration ratios of EPA to DHA were tested.^[15] In particular, a ratio of EPA to DHA of approximately 2:1, as found in EPAX 4020 TG, showed the most pronounced anti-inflammatory potency.

As already mentioned, increased intake of EPA/DHA reduces the concentrations of arachidonic acid (AA) in the cells, which leads to a desired reduction in the eicosanoids derived from AA and also in the pro-inflammatory cytokines.

Other discussed mechanisms for the anti-inflammatory effects of EPA and DHA is the involvement of these fatty acids in the modification of peroxisome proliferator-activated receptors (PPaRα and PPaRγ), which regulate gene transcription.

Another, still quite new explanation of the mechanism was given by Dr. Charles Serhan et al.^[16] from Harvard Medical School. This research team discovered two new families of lipid mediators that are produced in the body from the polyunsaturated omega-3 fatty acids. They called them "resolvins" and "protectins". These two classes of substances have a pronounced anti-inflammatory potency and also have tissue and neuroprotective properties. The mediators derived from eicospentaenoic acid (EPA) are called resolvins of the E series (resolvin E1), and the mediators derived from docosahexaenoic acid (DHA) are called resolvins of the D series. Anti-inflammatory eicosanoids are formed directly from EPA, which is not the case with DHA. However, DHA is directly converted to resolvin D 1 and protectin D1, which themselves have anti-inflammatory properties.

This newly discovered mechanism shows how a higher intake of EPA and DHA container stimulate the increased formation of these bioactive molecules. This deeper understanding of the causal relationships will be useful in the prevention of subliminal inflammatory conditions, known as silent inflammation, and will also generally provide new approaches in the prophylaxis and treatment of inflammation-related diseases.