controlling systemic inflammation naturally

Introduction
Mainstream media has been attributing the high incidence of diseases seen in the elderly population to simply the aging process and conventional medicine has not been proactively addressing the route of the problem.  However, there have been some key medical breakthroughs recently which have identified systemic inflammation as playing a central role in the development of age-related diseases such as Alzheimer’s disease, congestive heart failure and others.

What is Inflammation
Inflammation is the response of the immune system or body tissues to infection, irritation or injury. The characteristic signs of inflammation present as redness, swelling, heat, pain and dysfunction of the affected organ 1. 

Inflammation and Aging
Aging results in an increase of inflammatory cytokines (destructive cell signaling chemicals) that contribute to many degenerative diseases.  Rheumatoid arthritis is a classic autoimmune disorder where excess levels of cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and/or leukotriene B4 (LTB4) are known to cause or contribute to the inflammatory syndrome.

Chronic inflammation is also involved in diseases as diverse as atherosclerosis, cancer, heart valve dysfunction, diabetes, congestive heart failure and Alzheimer’s.  In aged people with multiple degenerative diseases, C-reactive protein is often sharply elevated, indicating the presence of an underlying inflammatory disorder.  When a cytokine blood profile is conducted in these feeble people, we usually find excess levels of one or more of the inflammatory cytokines (TNF-α, IL-6, IL-1β, LTB4).

Inflammation and Exercise
Inflammation is a common feature of muscle and its associated fascial covering due to blunt trauma sport injuries. Acute inflammation results in the interaction of the immune system and inflammatory cells which are mediated by proteins called interleukins (IL). Mobilization of various cytokines such as IL-1 and IL-6 activate neutrophils followed by recruitment of macrophages to the injured site 2.  Neutrophils appear to have a phagocytic role in addition to releasing proteases to clean up cellular debris 3. Neutrophils can also release cytotoxic and cytolytic molecules which cause destruction through lysis of muscle cells, fascia and surrounding tissues.  Overproduction of Tumor Necrosis Factor alpha (TNF-α), IL-1 and IL-6 are implicated in chronic inflammation of prolonged duration and can lead to extensive tissue damage.

What Should You Do
Science has unraveled a group of key nutrients found in dietary supplements that can help reduce the inflammation which occurs after exercise induced or traumatic injury in order to minimize the impact of tissue damage and allow the body's immune system to begin the repair process.  Evidence based supplements are discussed below.

Mixed Dietary Supplement
Phillips et al. (2003) conducted an experiment to see if markers of inflammation IL-6 and C-reactive protein (CRP) were attenuated after dietary supplements on postexercise muscle injury.  C-reactive protein (CRP), an immune system molecule, is an inflammatory marker serving as a diagnostic tool for predicting various disease states associated with inflammation 4.

Forty men were randomized to receive either placebo (high oleic sunflower oil) or a dietary supplement consisting of 300 mg mixed tocopherols, 800 mg of docosahexaenoate and 300mg of flavonoids (100 mg hesperetin and 200 mg quercetin) on a daily basis for 14 days. Three days postexercise, the control group saw increases in CRP and IL-6 whereas this rise was minimal in the supplemented group. By day 14, both groups showed decreases in both inflammatory mediators with the supplemented group having a statistically significant difference (P=0.05) on IL-6 and CRP (C-Reactive Protein).

Fish oil
Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are omega 3 polyunsaturated fatty acids (PUFA) which are capable of regulating the inflammatory process.  Human studies have shown that fatty acid metabolism is linked to the immune system through effects on eicosanoids (prostaglandins, leukotrienes, and thromboxanes) 5. Prostaglandins are regulators of the immune response and their formation is influenced by fatty acids which affect arachidonic acid (AA) metabolism. EPA and DHA compete with AA to reduce prostaglandin E2 and leukotriene B4 formation. In addition, these PUFA have the ability to reduce the capacity of monocytes to produce IL-1 and TNF-alpha which cause inflammation.
By reducing the amount of saturated fat in the diet and incorporating omega 3 PUFA, studies have shown that the immune and inflammatory process in the body can be regulated through modification of cytokines, ecosanoids and gene expression. But consumption of PUFA beyond 3 to 4 grams daily may impair immunity and result in increased destruction of lipid layer in cells (lipid peroxidation) and resultant free radical generation (oxidative species) causing a reduction in components of the immune system which protect the body from invasion by bacteria and viruses  (T-cell directed function, NK cell function, and macrophage activity) 6.  Therefore, consumption of other antioxidants may be required to reduce the overall rise in oxidant byproducts.

Boswellia
Boswellia and it's main constituent, boswellic acid, is derived from the dried gum resin of Boswellia carterii. A study done on rats was designed to assess the efficacy of boswellia extract on reducing adjuvant-induced arthritis in rats 7.  A single oral dose was administered daily for 7 days to measure edema and increased sensitivity to pain (hyperalgesia). At a dose of 0.45 g/kg/day there was significant reduction in pain by day 5 whereas a higher dose (0.9 g/kg/day) reduced pain at an early stage (5 to 24 hours) and on day 5. The researchers speculate that the hyperalgesia effect is due to boswellia's anti-inflammatory properties brought about by immune modulation. Boswellic acids can reduce the production of leukotriene B4, a substance involved in inflammation, by granulocytes and macrophages as well as slowing the movement of leukocytes to the site of inflammation.

Turmeric
Turmeric root contains volatile oil, diferuloyl methane (curcumin), demethoxycurcumin, and bisdemethoxycurcumin; all of which are known as curcuminoids 8. Curcumin, the lipid soluble component in turmeric, possesses anti-inflammatory, anticancer and antioxidant properties.  Curcumin has been shown to consistently block the activity of the transcription factor Nuclear Factor Kappa Beta (NF-kB) (a compound significant in the body’s inflammatory response) 9. Intraperitoneal injection of mice with curcumin has been shown to stimulate muscle differentiation and enhance the regeneration process after injury through inhibition of NF-kB expression on various inflammatory cytokines 10.  Curcumin also mediates the metabolism of arachidonic acid (AA) by inhibition of cyclooxygenase-2, an enzyme responsible for inflammation and pain. In addition, lipoxygenase, hyaluronidase, phospholipase and collagenase enzymes which also play a role in inflammation are inhibited. 

Vitamin B6
The active form of vitamin B6, pyridoxal 5'-phosphate (PLP), is a water soluble compound which may play a role in the etiology of inflammation. Kelly et al. (2004) found a direct dose response inverse relationship between C reactive protein (a marker for inflammation) and PLP on subjects with new ischemic stroke when compared with matched controls 11. Lower plasma PLP was associated with higher CRP levels. In another study, animals fed a B6 deficient diet showed greater infiltration of inflammatory cells in the diaphragm, masseter and heart muscles after infection with T. Spiralis, compared to mice fed a normal diet  and B6 deficient rats saw edema increase by 54% compared with weight-matched controls 12. Thiobarbituric acid reactive substances (which indicate the extent of lipid peroxidation) increased by 30 and 43% in the edematous tissue of B6 deficient mice. Collectively, the data shows that pyridoxine deficiency enhances inflammation 13.

Lactoferrin
Lactoferrin, an iron-binding protein derived from milk and processed whey, possesses a host of biological activities such as antibacterial, antitumor, anti-inflammatory, antiviral, antifungal, and immune modulation 14.  Neutrophils produce high levels of lactoferrin where it is stored in secondary granules and released during inflammation to contribute to it's physiologic properties.  In vitro and in vivo studies have shown that lactoferrin can modulate the immune system and correct cytokine imbalance by inducing anti-inflammatory cytokines IL-4 and IL-10, inhibiting the proinflammatory cytokines TNF-alpha and IL-1beta and downregulating NF-kB 15,16.  Orally administered lactoferrin is broken down in the gut to form a new peptide, lactoferricin with similiar antibacterial activities as the parent compound. Mice fed lactoferrin have shown an increase in IgA and IgG in the intestinal fluid and induction of IL-18 secretion in the small intestine of mice 17. IL-18 enhances activities of T helper-1 (Th-1) and natural killer (NK) cells.

Resveratrol
Resveratrol is naturally occuring polyphenolic compound produced by certain vines, pine trees, peanuts, grapes, and other plants. It has been studied for its antimicrobial, anti-inflammatory, anticancer, antioxidant and beneficial cardiovascular properties.

Resveratrol's vast anti-inflammatory properties have been elucidated by in vitro and in vivo studies: l. inhibition of COX-1 and COX-2 enzymes, 2. antioxidant, 3. inhibition of 5-Lipoxygenase (5-Lox), 4. inhibition of mediators of inflammation from macrophage, 5. inhibition of TNF-alpha, leukotrienes, histamines and eicosanoids from mast cells and 6. inhibition of protease and oxidant release from neutrophils 18.  

Inflammation is a complex process which involves cytokine signalling and kinases such as MAPKs, PKC, phosphoinositide-3-kinase etc. MAPKs phosphorylates (adds a phosphate (PO4) group to a protein or molecule) a variety of transcription factors (NF-kB and AP-1). Resveratrol inhibits the activation of these transcription factors and disrupts the signalling pathways required for initiation of the cascade towards inflammation. In addition, topical application of resveratrol can enhance wound healing by increasing connective tissue deposition and improving the overall integrity of the wound area.

Ginger
Ginger, a rhizome of the plant Zingiber officinale, has been used in traditional medicine for centuries as a stimulant, diuretic, diaphoretic and nausea. Today, interest in ginger lies in its anti-nausea and anti-inflammatory properties.  The active components of ginger include phenolic compounds, sesquiterpenes, galanolactone, gingesulfonic acid, zingerone, monoacyldigalactosylglycerols, and gingerglycolipids.  Ginger is able to modulate inflammation through various pathways 19.  It does this by inhibiting COX-1 and COX-2 enzymes, thus lowering prostaglandin E2 production, inhibiting 5-Lox thereby reducing leukotrienes and interfering with the induction of genes involved with inflammation. In addition to its anti-inflammatory property, ginger also possesses analgesic effects. One of the active components [6]-gingerol, given in doses of 25 mg/kg and 50 mg/kg, was administered to mice intraperitoneally 20.  The results revealed a reduction in the acetic acid-induced writhing response (in the late phase) comparable to the nonsteroidal anti-inflammatory drug indomethacin. The acetic writhing test is used to study a drug's peripheral analgesic property and since the late phase correlates with the inflammatory response and pain it was concluded that [6]-gingerol acts peripherally rather than centrally.

Cat's Claw
Cat's claw is a tropical vine that grows in rainforest and jungle areas in South America and Asia.
The bark and root contain active substances such as alkaloids, polyphenols, tannins and several other phytochemicals which possess anti-inflammatory and antioxidant activity.  A study conducted by Aguilar et al. (2002) compared a hydroalcoholic extract against an aqueous freeze-dried extract from the bark of cat's claw on carrageenan-induced paw edema model in mice. While both extracts significantly reduced edema, the hydroalcoholic extract (50mg/kg) produced an anti-inflammatory effect at a much lower dose than the freeze-dried extract (200mg/kg). Cat's claw mechanisms of action involves moderate to weak activity against COX-1 and COX-2 in vitro, strong antioxidant properties of it's proanthocyanidin content in scavenging various free radicals and suppression of TNF-alpha production 22.
But of the two Cat's claw species, Uncaria tomentosa and Uncaria guianensis, the latter has the most potent antioxidant and anti-inflammatory properties.

Superoxide Dismutase
Superoxide dismutase (SOD) is a naturally occurring enzyme found in the cytosol and mitochondria. Manganese is required for the mitochondrial form while copper and zinc is required for the cytosol form. SOD plays an important role in cellular antioxidant defenses.

SOD possesses potent free radical scavenging activity and this is thought to be one mechanism by which it interrupts the inflammatory cascade 23.  Another mechanism, shown in vitro, involves reduced movement of leukocytes suggesting a reduction in infiltration of inflammatory cells 24.  Orally administered SOD can attenuate muscle damage after injury by unregulating the expression of desmin, a peptide produced by skeletal, cardiac and smooth muscles. Desmin is important in linking the myofibrils in skeletal muscles and tissue cohesion. Because orally consumed SOD is degraded in the gastrointestinal tract, it is combined with wheat gliadin to act as a protective carrier. Vouldoukis et.al has shown increased antioxidant defences and improved cellular resistance to oxidative stress with the SOD-gliadin combination 25.

Conclusion
Nutritional intervention in sports related trauma can have a dramatic impact on the recovery of the affected organ. The link between the immune system and inflammation increases our understanding of how supplements can confer benefits without the adverse effects associated with conventional drug therapy. Acute inflammation, while beneficial to some extent can lead to chronic inflammation and the use of nutritional supplements is gaining popularity as a means of mitigating the destructive effect of the inflammatory response.

References
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