Antiinflammatory Aspects of n3 Fatty Acids

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Many experimental studies have provided evidence that incorporation of alternative fatty acids into tissues may modify inflammatory and immune reactions and that n-3 fatty acids in particular are potent therapeutic agents for inflammatory diseases. Supplementing the diet with n-3 fatty acids (3.2 g EPA and 2.2 g DHA) in normal subjects increased the EPA content in neutrophils and mono-cytes more than sevenfold without changing the quantities of AA and DHA. The anti-inflammatory effects of fish oils are partly mediated by inhibiting the 5-lipoxygenase pathway in neutrophils and monocytes and inhibiting the leukotriene B4 (LTB4)-mediated function of LTB5 (Figure 5). Studies show that n-3 fatty acids influence interleukin metabolism by decreasing IL-1,3 and IL-6. Inflammation plays an important role in both the initiation of atherosclerosis and the development of athero-thrombotic events. An early step in the atherosclerotic process is the adhesion of monocytes to endothelial cells. Adhesion is mediated by leukocyte and vascular cell adhesion molecules (CAMs) such as selectins, integrins, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). The expression of E-selectin, ICAM-1, and VCAM-1, which is relatively low in normal vascular cells, is upregulated in the presence of various stimuli, including cytokines and oxidants. This increased expression promotes the adhesion of monocytes to the vessel wall. The monocytes subsequently migrate across the endothelium into the vascular intima, where they accumulate to form the initial lesions of atherosclerosis. Atherosclerosis plaques have been shown to have increased CAM expression in animal models and human studies.

Diabetes is a major risk factor for coronary heart disease. EPA and DHA increase sensitivity to insulin and decrease the risk of coronary heart disease. Rheumatoid arthritis has a strong inflammatory component characterized by an increase in interleukin (IL)-1^. n-3 fatty acids decrease IL-1,3 as well as the number of swollen and painful joints. Supplementation with EPA and DHA, changing the ratio of n-6:n-3 of the background diet by increasing the n-3 and decreasing the n-6 intake, is now standard treatment for patients with rheumatoid arthritis along with medication in a number of centers around the world. Similarly, changing the background diet in patients with asthma has led to decreases in the dose of nonsteroidal anti-inflammatory drugs.

These studies suggest the potential for complementarity between drug therapy and dietary choices and that increased intake of n-3 fatty acids and decreased intake of n-6 fatty acids may lead to drug sparing effects. Therefore, future studies need to address the fatty acid composition and the ratio of n-6:n-3 of the background diet, and the issue of concurrent drug use. A diet rich in n-3 fatty acids and low in n-6 fatty acids provides the appropriate background biochemical environment in which drugs function.

Psychologic stress in humans induces the production of proinflammatory cytokines such as interferon gamma (IFN7), TNFa, IL-6, and IL-10. An imbalance of n-6 and n-3 PUFA in the peripheral blood causes an overproduction of proinflammatory cytokines. There is evidence that changes in fatty acid composition are involved in the pathophysiology of major depression. Changes in serotonin (5-HT) receptor number and function caused by changes in PUFAs provide the theoretical rationale connecting fatty acids with the current receptor and neurotransmitter theories of depression. The increased 20:4n-6/20:5n-3 ratio and the imbalance in the n-6:n-3 PUFA ratio in major depression may be related to the increased production of proinflammatory cytokines and eicosanoids in that illness. Studies have shown that EPA and DHA prolong remission, that is, reduce the risk of relapse in patients with bipolar disorder. There are a number of studies evaluating the therapeutic effect of EPA and DHA in major depression.

Earlier studies in rodents showed that ALA intake improved learning, memory and cognition. In Zell-weger's syndrome (a genetic neurodegenerative disease) high amounts of DHA early in life decreased somewhat the rate of progression of the disease. A number of studies have suggested that people who eat a diet rich in fish are less likely to develop Alzheimer's disease. Learning and memory depend on dendritic spine action assembly and DHA. High DHA consumption is associated with reduced risk for Alzheimer's disease, yet mechanisms and therapeutic potential remain elusive. In an Alzheimer's disease mouse model, reduction of dietaty n-3 fatty acid resulted in 80%-90% losses of the p85 alpha subunit of phosphoinositol 3-kinase and the postsy-naptic action-regulating protein drebrin as in the brain of patients with Alzheimer's disease. The loss of postsynaptic proteins was associated with increased oxidation without concomitant neuron or presynaptic protein loss. Treatment of the n-3 fatty acid restricted mice with DHA protected against these effects and behavioral deficits. Since n-3 fatty acids are essential for p85-mediated central nervous system insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases, where synaptic loss is critical, especially in Alzheimer's disease. A few case control studies suggest that higher EPA and DHA intake is associated with lower risk of Alzheimer's disease and severity of the disease. Inflammation is a risk factor for Alzheimer's disease. It remains to be determined whether low n-3 fatty acids, especially low DHA status, in patients with Alzheimer's disease is a causal factor in the pathogenesis and progression of Alzheimer's disease and other neurodegenerative diseases.

Cancer is characterized by inflammation, cell proliferation, and elevated IL-6 levels. Since EPA and DHA suppress IL-6, fish oil supplementation suppresses rectal epithelial cell proliferation and PGE2 biosynthesis. This was achieved with a dietary n-6:n-3 ratio of 2.5:1, but not with the same absolute level of fish oil intake and an n-6:n-3 ratio of 4:1. Case control studies in women with breast cancer support the hypothesis that the balance between n-6 and n-3 in breast adipose tissue plays an important role in breast cancer and in breast cancer metastasis.

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