Nutrition 411: Omega-3 Fatty Acids and Wound Healing

  The National Center for Health Statistics (NCHS) and National Center for Complementary and Alternative Medicine (NCCAM) conducted a survey in 2007 to determine the extent of complementary and alternative medicine use in America.¹ The findings indicated omega-3 fatty acid supplements were the most commonly used nonvitamin/nonmineral product among adults; 37% who had used natural products in the last 30 days had taken an omega-3 supplement for health reasons. The benefits of omega-3 fatty acid supplementation have been well documented for improving heart health and triglyceride levels. As a result, clinicians have been looking to broaden its use for managing the inflammatory response during wound healing. This article presents the key factors involved in the inflammatory process and the role omega-3 fatty acids play in wound healing.

Omega-3 Fatty Acid Basics

  Dietary fat is comprised of fatty acids that contain various numbers of carbon atoms and double bonds. These chemical properties give rise to short- or long-chain fatty acids that are saturated (no double bonds) or unsaturated. Unsaturated fatty acids are either monounsaturated (one double bond) or polyunsaturated (multiple bonds). The two types of polyunsaturated fatty acids (PUFAs), omega-3 and omega-6, are distinguished by the location of the first double bond from the methyl end of the fatty acid. Omega-3 and omega-6 fatty acids are essential fatty acids—ie, they are not synthesized in the body and thus must be obtained from the diet. In general, omega-6 fatty acids, found in vegetable oils, dairy products, meat, and processed foods, are abundant in the diet. Omega-3 fatty acids include the plant-derived a-linolenic acid (ALA) and marine-derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). They are found in less-consumed foods such as nuts, seeds, and fish; therefore, they are not as common in a typical Western diet.

  Epidemiologic, clinical, and experimental studies have shown multiple health benefits of omega-3 fatty acids. In particular, EPA and DHA may confer protective effects against coronary heart disease. Several mechanisms may be responsible for the cardioprotective effects of EPA and DHA, including prevention of arrhythmias, lowering heart rate and blood pressure, decreasing platelet aggregation, and lowering plasma triglyceride levels. Additional putative beneficial effects of omega-3 fatty acids have been demonstrated in inflammatory conditions such as rheumatoid arthritis and for mental health. High concentrations of DHA are found in the brain and other parts of the central nervous system; prospective studies have linked both all-cause dementia and Alzheimer’s disease to decreased fish intake and low plasma phospholipid DHA levels.²

Inflammation: Key Factors

  The complexities of the wound healing process are reflected in nutrition interventions. The first phase of healing, the inflammatory response, is the body’s initial reaction to injury. Inflammation is essential for normal healing because it initiates the cascade of molecular and cellular processes necessary for a wound to heal. However, unresolved or chronic inflammation can delay wound healing; thus, cellular communication and activity must be highly regulated and controlled. Initially, eicosanoids, key mediators and regulators of inflammation, provide this control. Eicosanoids include prostaglandins, thromboxanes, leukotrienes, and other hydroxyl fatty acids. They are generated from PUFAs and are involved in determining the intensity and duration of the inflammatory phase.³

  PUFAs are essential components of the phospholipid bilayer, regulate a wide range of bodily functions, and are precursors to several molecules involved in the inflammatory process. PUFAs are classified by their chemical structure and are characterized as either an omega-3 or omega-6 fatty acid. Omega-6 arachidonic acid is the major substrate for eicosanoid synthesis. The eicosanoids derived from arachidonic acid originally were described as proinflammatory—ie, they play an important role in early inflammation. However, new research has shown that some arachidonic acid-derived eicosanoids elicit both pro- and anti-inflammatory effects.⁴

  EPA and DHA are believed to elicit anti-inflammatory protective effects by acting as antagonists to arachidonic acid metabolism and inhibiting the production of inflammatory eicosanoids, adhesion molecules, and cytokines.⁴ Additionally, omega-3 fatty acids alter membrane fluidity and transcription factor activation, modify gene expression, and influence the activity of membrane proteins. Furthermore, EPA and DHA have been shown to synthesize resolvins, a new family of lipid mediators. Additionally, through several chemical reactions, DHA gives rise to another type of mediator, protectin D. Several studies have shown resolvin and protectin D can prevent and resolve inflammation.⁵ Many researchers have high hopes that these mediators will be able to explain many of the anti-inflammatory properties of the omega-3 fatty acid family. Lastly, EPA and DHA have been shown to inhibit the main proinflammatory cytokines, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF). These cytokines, specifically IL-1 and TNF, can cause bone, muscle, and tissue mass loss during prolonged inflammation.⁶

Omega-3s and Wounds: What the Research Says

  Several recent studies analyzed the effect of omega-3 fatty acids on lipid mediator levels and wound healing time. However, the phenomenon of proinflammatory cytokine alteration and the effect of omega-3 fatty acid supplementation are not clearly understood.

  In a 2008 study,⁷ several small blisters were created in 30 healthy human participants and analyzed after 4 weeks. The study group was given 1.6 g EPA and 1.2 g DHA per day, while the placebo group received mineral oil. Surprisingly, the time to complete wound healing did not differ significantly between the two groups. In fact, healing took 1 day longer in the study group. Additionally, after 24 hours of blister formation, blister fluid taken from the active group had a higher level of proinflammatory cytokines. This finding may suggest a more vigorous early inflammatory reaction seen with omega-3 supplementation. A similar subsequent study⁸ using rats found an increased amount of inflammatory cells in the study group that was given linseed or fish oil. The researchers proposed that an unusually strong inflammatory response may be the reason for delayed wound healing. Importantly, the study noted that PUFA can alter collagen formation, which needs to be minimized to prevent fibrosis in wounded skin. The study illustrated that animals supplemented with omega-3 fatty acid had increased collagen deposition on granulation tissue. This is important when there is potential for excessive scar formation.

  Evidence suggests that EPA/DHA supplementation may increase plasma fatty acid levels and affect the production of proinflammatory mediators that regulate the inflammatory process. However, more research is needed to clarify if this is beneficial or detrimental to wound healing. Omega-3 Sources (see Table 1)

  The human body can make all of the fatty acids it requires except omega-3 ALA and omega-6 linoleic acid (LA), which must be obtained through the diet. ALA is contained in certain seed oils (eg, canola and flaxseed) and nuts (eg, walnuts). Although it can undergo conversion to EPA in vivo, these conversion rates may be low. The most concentrated source of EPA and DHA from food is fatty fish such as sardines, salmon, and herring. Importantly, some species of fish (notably shark, king mackerel, swordfish, and tilefish) may contain high levels of methyl mercury, dioxins, polychlorinated biphenyls (PCBs), and other environmental contaminants. However, studies⁹ in adults (excluding pregnant women) show that the benefits of consuming one to two servings of fish per week exceed the potential health risks associated with contaminants such as methyl mercury and PCBs. Consuming commercially prepared fried fish, which typically contain low levels of EPA and DHA, is unlikely to lower cardiovascular risk. Farmed fish contain potentially similar amounts of EPA and DHA as wild fish; however, farmed fish are captive and can accumulate pesticides, antibiotics, and other pollutants. Although the selection of foods supplemented with EPA and DHA (eg, eggs and salad dressings) is growing, additional studies are needed to confirm the health benefits of consuming such products.

  In addition to eating fatty fish at least two times a week, the American Heart Association^10,11 recommends consuming a daily fish oil supplement that provides 0.9 to 1.0 g EPA and DHA. A 1-g fish oil capsule comprises approximately 0.3 g EPA and DHA; therefore, an individual would need to consume three capsules per day in order to attain the recommended amount. Because supplements are not regulated by the FDA, each brand, and possibly each batch, contains different amounts of EPA and DHA, so it is important to read the label and look specifically for the EPA and DHA content. The US Food and Drug Administration¹¹ (FDA) has concluded that up to 3 g omega-3 fatty acid from dietary sources is “generally recognized as safe.” For those patients who avoid fish, consumption of 1.5 to 3 g of ALA from dietary sources such as flaxseed, canola oil, or walnuts should be encouraged. For patients with very high triglyceride levels, prescription grade omega-3 capsules are available under the brand name Lovaza® (GlaxoSmithKline). Each Lovaza capsule contains .85 g EPA and DHA, which is significantly more than over-the-counter fish oil supplements.¹² In addition, because Lovaza is FDA-approved, it is subject to more rigorous oversight concerning purity, consistency and claims than over-the-counter products.

Potential Drug Interactions

  Omega-3 fatty acids are typically well tolerated; the main complaints are a fishy aftertaste and gastrointestinal disturbances. Freezing the capsules before ingestion can sometimes alleviate the aftertaste. Although more research is needed, omega-3 fatty acids may exert a dose-related effect on other medications. Some interactions are mutually beneficial, having a synergistic effect with the drug, while others have an antagonistic effect. For example, omega-3 fatty acids may reduce toxic side effects associated with cyclosporine (Sandimmune®, Novartis) therapy in transplant patients.¹¹ Additionally, if using Tegison (Hoffman-LaRoche) in conjunction with omega-3 fatty acids, symptoms of psoriasis may improve. Lastly, cholesterol-lowering medications such as statins may work more efficiently with the use of omega-3 fatty acids. A potential negative side effect has been documented during the use of blood thinning medications, such as aspirin, warfarin (Coumadin, Bristol-Myers Squibb), and clopedigrel (Plavix, Sanofi-Aventis). Omega-3 fatty acids may increase the effects of these medications; however, no cases of abnormal bleeding have been documented. Table 2 summarizes these interactions.

Putting It All Together

  The use of omega-3 fatty acids for hyperlipidemia, hypertension, rheumatoid arthritis, and coronary heart disease is well documented and frequently beneficial. However, its usage in the treatment of wounds is not as clear. More research is needed to determine if this supplement should be added to protocols. However, what is clear is that wound care practitioners must ask patients about any supplements they may be self-prescribing. Omega-3 supplementation is so common that patients may have added it to their regimen without clinician knowledge or advice. Treatment of any chronic or nonhealing wound always mandates a conversation about nutrition along with a nutritional screening. Referral to a registered dietitian may be arranged, if necessary for more in-depth assistance with any nutritional problems.

 Nancy Collins, PhD, RD, LD/N, FAPWCA, is founder and executive director of RD411.com and Wounds411.com. For the past 20 years, she has served as a consultant to healthcare institutions and as a medico-legal expert to law firms involved in healthcare litigation. Colleen Sulewski is a dietetics and nutrition intern at Florida International University in Miami, FL. She is a future registered dietitian and currently is employed by RD411.com, a web site for nutrition and healthcare professionals. Correspondence may be sent to Dr. Collins at NCtheRD@aol.com. This article was not subject to the Ostomy Wound Management peer-review process.

1. Omega-3 Supplements: An Introduction. Available at: http://nccam.nih.gov/health/omega3/introduction.htm. Accessed June 3, 2011.

2. Schaefer EJ, Bongard V, Beiser AS, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006;63(11):1545–1550.

3. McDaniel JC, Massey K, Nicolaou A. Fish oil supplementation alters levels of lipid mediators of inflammation in microenvironment of acute human wounds. Wound Repair Regen. 2011;19(2):189–200.

4. Calder P. Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale. Biochimie. 2009;91(6):791–795.

5. Calder P. Omega-3 fatty acids from fish and plants: same family, different biological activity. Nutri Ther Metab. 2010;28(3):101–109.

6. Calder P. Polyunsaturated fatty acids and inflammation. Prost Leuk Ess Fatty Acids. 2006;75:197–202.

7. McDaniel J, Belury M, Ahijevych K, Blakely W. Omega-3 fatty acids effect on wound healing. Wound Repair Regen. 2008;16(3):337–345.

8. Otranto M, Do Nascimento AP, Monte-Alto-Costa A. Effects of supplementation with different edible oils on cutaneous wound healing. Wound Repair Regen. 2010;18(6):629–636.

9. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006;296(15):1885–1889.

10. American Heart Association. Fish 101. Available at: www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/Fish-101_UCM_305986_Article.jsp. Accessed June 3, 2011.

11. Covington M. Omega-3 fatty acids. Am Fam Phys. 2004;70(1):133–140.

12. Collins N, Tighe A, Brunton S, Kris-Etherton P. Differences between dietary supplementation and prescription drug omega-3 fatty acid formulations: a legislative and regulatory perspective. J Am Coll Nutr. 2008;27(6):659–666.

13. Drug Interactions. Available at: http://heart-disease.emedtv.com/omega-3/omega-3-drug-interactions-p2.html). Accessed June 3, 2011.