Omega-3 and inflammation. What and how happens in the body during it?
Probably, it would be difficult to find a person who has not faced inflammation at least once in his life. Currently, probably the simplest and most common way to treat inflammation and relieve the pain caused by it is with non-steroidal anti-inflammatory drugs (NSAIDs), i.e. aspirin, ibuprofen, diclofenac, etc. However, few know that EPR and DHA can be just as effective as the previously mentioned preparations, especially in treating chronic inflammation (such as rheumatoid arthritis) and suppressing the pain caused by it. How is it going?
What happens during ignition?
Regardless of the cause of the inflammation, its active phase always includes four main stages:
1. Blood supply to the affected area increases.
2. Capillary permeability increases. In other words, the intercellular spaces between the cells that make up the capillary (endothelium) increase, that is, retraction of the endothelial cells occurs. Thanks to this, large molecules, which under normal conditions cannot pass from the capillary through the endothelium, easily do so. In this way, water-soluble inflammatory mediators enter the inflamed tissue.
3. Migration of leukocytes takes place. Leukocytes, under the influence of certain substances (chemoattractants) and endothelial adhesion (adhesion) molecules diffused from the site of inflammation, travel from the capillaries to the tissues. Once inside the tissues, they move towards the site of inflammation.
4. Release of inflammatory compounds (mediators) from leukocytes. Depending on the type of cells affected by the inflammation, the origin of the stimulus that caused the inflammation, the anatomical location of the damaged tissue and the stage of the inflammatory response, the leukocytes that have traveled to the site of inflammation release various inflammatory compounds: lipid mediators (e.g. prostaglandins, leukotirneus), peptide mediators (e.g. cytokines), reactive oxygen species (eg superoxide radicals), amino acid compounds (eg histamine) and various enzymes (eg proteases). All of these compounds normally serve as host defenses against an inflammatory stimulus. However, when they are produced or regulated incorrectly, they can damage healthy tissue and cause disease. Some of the aforementioned inflammatory mediators can enhance the inflammatory process, for example by acting as chemoattractants. Others, such as interleukin-6, can leave inflamed tissue and cause systemic effects.[1]
What symptoms accompany inflammation?
These include redness, swelling, heat, pain and loss of function. For example, if you twist your leg, it becomes swollen, red, hot and painful, and its function is impaired - it becomes difficult to walk.
How do pain and inflammation medicines (non-steroidal anti-inflammatory drugs) work?
To understand how omega-3s help reduce inflammation and pain, we first need to delve into the somewhat simpler mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs).
NSAIDs work by blocking enzymes called cyclooxygenases (COX). These enzymes produce eicosanoids from arachidonic acid (belongs to the omega-6 family) contained in membrane phospholipids, which regulate many normal functions of the body (protection of the stomach lining, kidney function, blood clotting, etc.). Some eicosanoids have anti-inflammatory effects, causing pain and fever. For quite a long time, it was believed that COX-1 is responsible for eicosanoids intended to regulate physiological body functions, and COX-2 is responsible for inflammatory eicosanoids, which is activated only during inflammation and is normally found in only a few organs and tissues (kidneys, brain, female reproductive organs). . There is increasing evidence that COX-2 is very widespread in the body and can be found in many organs, with a few exceptions such as the heart.[2] This knowledge forces a rethinking of the assessment of COX-1 and COX-2, the benefits/harms of NSAIDs, and encourages the realization that the role of these cyclooxygenase isozymes and their blockade must be evaluated in a much more complex way.
How do NSAID side effects occur?
The goal of NSAIDs is to block COX-2 as selectively as possible and thus, by reducing the amount of inflammatory eicosanoids (prostaglandins) produced by it, suppress pain and inflammation. Nevertheless, the use of NSAIDs causes a number of side effects. Most of them are due to the fact that NSAIDs block not only COX-2 (the "bad"), but also COX-1 ("the good"). This reduces the prostaglandins produced by COX-1, which perform such important functions as the protection of gastric mucosal cells, regulating kidney function, vascular lumen, bronchial lumen, blood coagulation and many others.[3] For these reasons, the use of NSAIDs is associated with an increased risk of bleeding from the gastrointestinal tract, kidney dysfunction, difficulty breathing, rashes, fertility problems, etc. it is responsible for the synthesis of prostaglandins that cause inflammation and pain), will prevent most of the side effects of NSAIDs, especially gastrointestinal bleeding. It worked, but only partially. Another problem arose: the use of selective COX-2 inhibitors greatly increased the risk of thrombus formation and the number of cardiovascular events (strokes, heart attacks, thrombosis).
Why did this happen? Because the balance of COX-1 and COX-2 and the eicosanoids produced by them, which have the opposite effect, was disturbed: the prostacklin produced due to the effect of vascular endothelium COX-2 dilates blood vessels and inhibits platelet aggregation (adhesion, sticking), while COX-1 in platelets produces thromboxane A2, which has the opposite effect of constricting blood vessels and promoting platelet aggregation. By blocking the production of prostacyclin with drugs, there is nothing left to resist the effects of troboxan A2 and it becomes easier for thrombi to form.[4]
Regarding the inflammation mechanism, it is also very important to mention the enzymes of the lipoxgenase (LOX) family, which also metabolize fatty acids. Lipoxygenase produces leukotrienes from arachidonic acid. They are classified as mediators of inflammation and have a particularly prominent role during acute inflammation and allergy. Leukotrienes cause vascular and bronchial smooth muscle spasms, increase the permeability of the vascular wall, many of them are produced in ischemic heart disease, bronchial asthma, allergies, etc. t[5]. The use of NSAIDs does not reduce leukotriene production, and in some cases even increases it.[6] It is believed that this may lead to such side effects of NSAIDs as shortness of breath, allergic reactions. Thus, NSAIDs have a number of disadvantages.
How does omega-3 affect inflammation?
Omega-3 fatty acids, like arachidonic acid, are found in phospholipids in the cell membrane and compete as COX and LOX substrates. EPR, like arachidonic acid, is used to produce COX and LOX eicosanoids, but these are much less pro-inflammatory than those derived from arachidonic acid.[7] It is also very important to mention that with the help of cyclooxygenase and lipoxygenase, resolvins and substances similar to them, such as protectins, are synthesized from EPR and DHA, which not only have an anti-inflammatory effect, but also help the body to recover, promoting faster removal of inflammatory residues and mucous membranes. antimicrobial protection.[8][9][10] Interestingly, cyclooxygenases, blocked by NSAIDs and unable to bind arachidonic acid, are able to synthesize resolvins from EPA and DHA.[11] Additionally, DHA has been shown to inhibit COX-2 synthesis without affecting COX-1 synthesis.[12]
1] Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients. 2010 Mar;2(3):355-74. doi: 10.3390/nu2030355. Epub 2010 Mar 18. PMID: 22254027; PMCID: PMC3257651.
[2] Zidar N, Odar K, Glavac D, Jerse M, Zupanc T, Stajer D. Cyclooxygenase in normal human tissues--is COX-1 really a constitutive isoform, and COX-2 an inducible isoform? J Cell Mol Med. 2009 Sep;13(9B):3753-63.
[3] Miller, Stephen B. "Prostaglandins in health and disease: an overview." Seminars in arthritis and rheumatism. Vol. 36. No. 1. WB Saunders, 2006.
[4] Bing, Richard J., and Magdalena Lomnicka. "Why do cyclo-oxygenase-2 inhibitors cause cardiovascular events?" Journal of the American College of Cardiology 39.3 (2002): 521-522.
[5] Jo-Watanabe A, Okuno T, Yokomizo T. The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders. Int J Mol Sci. 2019 Jul 22;20(14):3580. doi: 10.3390/ijms20143580. PMID: 31336653; PMCID: PMC6679143.
[6] Robinson DR. Eicosanoids, inflammation, and anti-inflammatory drugs. Clin Exp Rheumatol. 1989 Sep-Oct;7 Suppl 3:S155-61. PMID: 2691152.
[7] Bagga D, Wang L, Farias-Eisner R, Glaspy JA, Reddy ST. Differential effects of prostaglandin derived from omega-6 and omega-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci US A. 2003 Feb 18;100(4):1751-6. doi: 10.1073/pnas.0334211100. Epub 2003 Feb 10. PMID: 12578976; PMCID: PMC149905.
[8] Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008 May;8(5):349-61. doi: 10.1038/nri2294. PMID: 18437155; PMCID: PMC2744593.
[9] Kohli P, Levy BD. Resolvins and protectins: mediating solutions to inflammation. Br J Pharmacol. 2009 Oct;158(4):960-71.
[10] Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008 May;8(5):349-61. doi: 10.1038/nri2294. PMID: 18437155; PMCID: PMC2744593.
[11] Serhan, Charles N., et al. "Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals." The Journal of experimental medicine 196.8 (2002): 1025-1037.
[12] Massaro M, Habib A, Lubrano L, Del Turco S, Lazzerini G, Bourcier T, Weksler BB, De Caterina R. The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKC epsilon inhibition. Proc Natl Acad Sci US A. 2006 Oct 10;103(41):15184-9. doi: 10.1073/pnas.0510086103. Epub 2006 Oct 3. Erratum in: Proc Natl Acad Sci US A. 2007 May 1;104(18):7729. PMID: 17018645; PMCID: PMC1622797.
[13] Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients. 2010 Mar;2(3):355-74.
[14] Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients. 2010 Mar;2(3):355-74.
[15] Ye J, Ghosh S. Omega-3 PUFA vs. NSAIDs for Preventing Cardiac Inflammation. Front Cardiovasc Med. 2018 Oct 23;5:146. doi: 10.3389/fcvm.2018.00146. PMID: 30406113; PMCID: PMC6205954.
[16] Maroon, Joseph Charles, and Jeffrey W. Bost. "ω-3 Fatty acids (fish oil) as an anti-inflammatory: an alternative to nonsteroidal anti-inflammatory drugs for discogenic pain." Surgical neurology 65.4 (2006): 326-331.