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Natural Approaches to Controlling Inflammatory Disease
By Jason Barker, ND, Chris Meletis, ND
Phone: (303) 382-9200
Visit: drjasonbarker.com
- Inflammation and the Disease Process
- Anti-Inflammation Diets
- Polyunsaturated Fatty Acids and Lymphocyte Functions
- Vitamin B6 and Inflammation
- Vitamin E, Zinc, and Magnesium
- Cat’s Claw
- Propolis
- Boswellia
- Conclusions
- References
Inflammation is simply a physiologic response process generatedby the body in response to injury, infection, or irritation.In acute stages, the inflammatory process is vital to thehealing process; however, chronic inflammation can increase disease-associated morbidity. New insights into the chronic inflammatoryprocess now provide evidence that this mechanism is anegative contributor to an ever-expanding list of chronic conditions,including Alzheimer's disease, cardiovascular diseases,diabetes, asthma, cancer, and even depression.As inflammation is increasingly acknowledged as a main precursorto morbidity in the pathology of chronic disease, medicineis elucidating both the effects of inflammation prior to clinicaldisease manifestation and preventative treatments geared towardreversal and attenuation of symptoms. Natural medical therapiesdirected toward anti-inflammatory effects have become moreintensely researched in the last several years, providing significantinsight into the role of inflammation in disease and offeringoptions for effective preventative and symptomatic treatment.
Inflammation and the Disease Process
The inflammatory process is now being associated with severaldiseases in which an inflammatory component was previouslyunknown. Coronary artery disease, major depression, and cancerare associated with an increased level of interleukin-1 (IL-1), apro-inflammatory cytokine, while elevated IL-1 levels and pro inflammatoryleukotriene (LT) B-4, most notably produced byomega-6 fatty acids, similarly characterize diseases such asarthritis, Crohn’s disease, ulcerative colitis, and systemic lupuserythematosis.1 Recent evidence indicates that inflammationplays a pivotal role in the origins and complications ofatherosclerotic and type 2 diabetic disease, linked by C-reactiveprotein (CRP), plasminogen activator inhibitor-1, and homocysteine.These nonconventional risk factors are now known asmarkers indicative of general low-grade inflammation, vascularinjury, and thrombotic processes.2
Chronic inflammation is believed to be an associated risk factorfor cancer in the human body in the bowel and rectum. Localizedinflammatory processes incite numerous pro-oxidativeenzymes (e.g., the reduced form of nicotinamide adenine dinucleotidephosphate [NADPH] oxidase, nitric oxide synthase) thatreact among themselves and with other reactive oxygen species to create an environment that is rich in highly reactive, pro-oxidative species. These oxidants damage DNA, leading to mutations, and may activate oncogenes and/or inactivatetumor-suppressor proteins, allowing carcinogenic processes to occur.
Other causes of localized chronic inflammatory-induced tumorgrowth that have been proposed include an oxidative processthat inhibits cellular apoptosis, cellular switching to a glycolyticmetabolism, and neovascular genesis and vasorelaxation that caninhibit recruitment of immune cells, all of which act collectivelyas an opposing force to the normally rapid cytotoxic response.3Studies on these topics these lend credence to the concept of preventativecancer treatment via modulating chronic inflammatoryconditions. Much of the literature on using fish oil as an anti inflammatoryapproach to treating chronic inflammatory diseasesshows significant benefits that include lowered diseaseactivity and decreased use of anti-inflammatory medications.
Anti-Inflammatory Diets
The anti-inflammatory diet, although it is not a recent developmentin preventing and treating inflammatory diseases, serves asthe cornerstone for mitigating the generalized, chronic inflammatoryresponse. This treatment is applied in many forms, differingfrom practitioner to practitioner. What is consistent in the variousforms of the anti-inflammatory diet is strict avoidance offoods that contain high amounts of arachidonic acid (AA), themain precursor of the negatively associated inflammatory cascadeprocess. Metabolites of AA include platelet activating factor,prostaglandins (PGs), LTs, and thromboxanes, which are closelyinvolved in both acute and chronic inflammatory responses.
The rate-limiting step in the creation of these inflammatorymetabolites is the release of AA from membrane phospholipids,which are catalyzed by the enzyme phospholipase A2. The clinical implications associated with imbalanced intake andmetabolism of the two essential fatty acids (EFAs), linoleic andalpha-linolenic acids, are directly related to their byproduct concentrationsin the membrane phospholipid layer. Levels of theselong-chain polyunsaturated fatty acids (arachidonic, eicosapentaenoic,and docosahexaenoic acids) may be affected by diet anddisease and can alter the severity, character, and intensity of systemicinflammatory processes.4
An alteration or loss of regulation of the AA cascade leads to achronic inflammatory state, which characterizes numerous physicaldisorders. A frequently indicated offender to be removed from the diet is red meat, a significant source of linoleic acid(LA), and its product AA. Another source of dietary inflammationis hydrogenated foods, which often have an increasedamount of LA and a decreased amount of the beneficial alphalinolenicacid (ALA). Numerous studies highlight a link betweenfoods that are high in omega-6 fatty acid and decreased intake ofomega-3 fatty-acid–rich foods.5 Dietary gluten and lectins arealso recognized as common triggers of inflammation.
It is theorized that humans evolved on a diet consisting of a 1:1ratio of omega-6 to omega-3 fatty acids. Today, the typical Westerndiet consists of a ratio between 10:1 and 25:1 and, in somecases, this ratio may be as high as 40:1. It is this imbalanced fatty acidratio that is linked to chronic inflammatory health problems.
A common misconception is that all commonly consumedomega-6 fatty acids (LA, AA, and gamma linolenic acid [GLA])are unhealthy, when the reality is that only excessive intake ofLA and AA (combined with a decreased intake of omega-3 fattyacids) contribute to chronic inflammation because these fattyacids are necessary for essential functions in the body.
High LA levels inhibit the delta-6-desaturase (D6D) enzyme,which is both the initial and rate-limiting enzyme in both theomega-6 and omega-3 fatty-acid pathways. This reduces furtherLA breakdown. In addition, because LA is not metabolized further,dihommo-gamma linolenic acid (DGLA), which is the precursorto GLA, is not formed. DGLA, in turn, is the precursor of anumber of beneficial eicosanoids that are important for optimalcell functioning. GLA has considerable health benefits and is notlinked to the problems associated with an unbalanced fatty-acidprofile.
Polyunsaturated Fatty Acids andLymphocyte Functions
The inflammatory mediators (PGs and LTs) that are producedvia polyunsaturated fatty acid (PUFA) metabolism can directlyinfluence the behavior of inflammatory immunologic cells andtheir production and balance of cytokines. Increased consumptionof omega-3 PUFAs displaces the amount of AA in cellularmembranes and thereby limits the production of pro inflammatoryeicosanoids. It is believed that acquired immunologic factorsare affected by omega-3 PUFA intake and incorporation into cellularmembranes and that fatty acids may stimulate someimmune activity by way of noneicosanoid-dependent mechanisms.6
Fish oil (a rich source of omega-3 PUFA) supplementation inanimals results in positively associated altered lymphocyte function,decreased macrophage-borne pro inflammatory cytokines,and pacification of autoimmune disease symptomatology. Inhuman subjects, dietary additions of omega-3 PUFAs have led todecreased monocyte and neutrophil chemotaxis and productionof pro inflammatory cytokines.7
Inflammatory-type diseases are amenable to fatty-acid replacementtherapies because the composition of fatty acids in lymphocytesand other immune cells are modified by both bodily-fatamounts and types of fatty acids available for eicosanoid production.Fatty acids such as arachidonic, alpha-linolenic, eicosapentaenoic,oleic, linoleic, conjugated linoleic, gamma-linolenic,dihomo-gamma-linolenic, and docosahexaenoic, all have the abilityto influence inflammatory responses that are associated withlymphocyte proliferation and cytokine production, as well as naturalkiller (NK)–cell activity.8
Cytokine production is reduced by omega-3 PUFAs, decreasingthe severity of the cytokine-related disease processes. Becausecytokine production and function are part of a normal hostdefense, they are necessary. Consumption of PUFAs in excess of3–4 g per day may lead to impairment of the immune response,however. Increased consumption of PUFAs may also lead toincreased lipid peroxidation and resultant oxidative species causinga reduction in T-cell directed function, NK cell function, andmacrophage activity.9 Consuming other sources of antioxidants,such as vitamin E, may mitigate increased oxidation due to consumptionof PUFAs.
Vitamin B6 and Inflammation
Vitamin B6 (pyridoxine) plays several roles in the etiology andpathogenesis of chronic inflammation and inflammatory diseases.Pyridoxine is water-soluble and is preferentially absorbedin an acidic milieu in the proximal small intestine via simple diffusion.This vitamin’s role in inflammation can be observed on anumber of metabolic levels and in various pathologies.
In one study, pyridoxine-deficient rats developed increasedconcentrations of thiobarbituric acid reactive substances (indicatorsof lipid peroxidation) up to 30–43 percent, suggesting anenhanced inflammation response caused by pyridoxine deficiency.10 In another study, median pyridoxine levels were significantlylower in human patients with inflammatory bowel disease(IBD) compared to controls and were even lower in patients withactive IBD compared to those whose disease was quiescent. Inaddition, lower pyridoxine levels were positively correlated withCRP serum levels, and hyperhomocysteinemia occurred morefrequently in patients with lower pyridoxine levels.11
Suboptimal levels of vitamin B6 are associated with increasedrisk for cardiovascular disease and rheumatoid arthritis. The reasonsfor this are not evident and a clear pathophysiologic picturehas not emerged for these two conditions, other than the inflammatoryreaction shared by both diseases. In one study, decreasedlevels of plasma pyridoxal 5¢-phosphate, the active form of vitaminB6, were associated with higherlevels of CRP independent of total plasma homocysteine. Theresearchers hypothesized that suchevidence may indicate that vitaminB6 deficiency contributes to chronicinflammatory processes.12
Another aspect of inflammationin which vitamin B6 is involved isfatty-acid metabolism. Inhibition ofD6D, which is both the initial andrate-limiting enzyme in both the omega-6 and omega-3 fatty-acid pathways, can result from vitaminB6 deficiency.13 In addition, because LA is not metabolizedfurther, GLA, which is the precursor to DGLA, is not formed.DGLA, in turn, is the precursor for a number of beneficialeicosanoids that are important for optimal cell functioning andproduction of PGE1, an anti-inflammatory PG.
Vitamin E, Zinc, and Magnesium
Other nutritional factors that are involved in positive up regulationof D6D include zinc, magnesium, and vitamin E. In one study,the enzymatic activity of D6D was increased at twice that of baselinelevel in subjects when their vitamin E microsomal membraneconcentrations were increased, reflecting the vitamin’s role in controllingthe membranous metabolism of PUFAs.14
In addition, zinc has been shown to assist in converting LA toGLA via D6D, and a deficiency of zinc produced an EFA deficiencyand down regulation of D6D.15 Magnesium deficiencycontributed to decreased formation of D6D molecules, resultingin a less-rapid conversion of LA to GLA in liver microsomes.16
By supplying patients with proper nutritional doses of theseenzymatic cofactors, efficient activation of this D6D can inducecomplete fatty-acid metabolism and production of noninflammatoryfatty-acid products, helping to reducing chronic inflammatorypatterns further.
Cat’s Claw
Cat’s claw (Uncaria tomentosa) is a medicinal plant that is nativeto the Amazon River basin, with a history of traditional use forinflammatory conditions. Two active compound groups, alkaloidsand flavanols, are presumed to be the major effector compounds.17
Studies of cat’s claw have utilized two species, Uncaria guianensisand Uncaria tomentosa and both are considered to be equiactivebut, currently, U. tomentosa has been more well-researched.A pulverized bark fraction of Uncaria tomentosa inhibited tumornecrosis factor–alpha (TNF-a) production by approximately65–85 percent and has acted as a potent antioxidant.18 These effects, immunomodulation of TNF-a and anti oxidative abilities,are widely documented in the literature. What is more, the anti inflammatoryeffects of this plant have been demonstratedrecently.
In test subjects with osteoarthritis of the knee, a comprehensivestudy was undertaken to determine the adverse-effect, pain,medical, and subject-assessment scores of patients who took a purified extract of the herb . Theresearchers noted an absence ofnegative effects on red blood–cellindices and liver function or otherside-effects compared to placebo.
In the Uncaria-t reated group,activity-associated pain, medicaland subjective assessment scoreswere “significantly” reduced within1 week of therapy at doses that achieved a level of 13.6–21.7 µg per mL of each subject’s blood and lipopolysaccharide-induced PGE2 synthesis was inhibited at a concentration higher than necessary to mitigate TNF-a production as had been explained in previous studies.19
In another study, an extract of Uncaria tomentosa was given topatients with active rheumatoid arthritis and who were undergoingsulfasalazine or hydroxychloroquine treatment in a 52-week,two-phase study. Twenty-four (24) weeks of treatment with thecat’s claw extract resulted in a decreased amount of painful jointsin treated subjects compared to those who were on a placebo(53.2 percent versus 24.1 percent) with minor side-effects, none ofwhich were listed.20
Cat’s claw is emerging as an effective botanical medicine that canbe used for treating various inflammatory states and conditions,producing positive effects and few side-effects. The anti-inflammatoryproperties of this herb are undergoing further investigationand continued research promises to provide even more specificexplanations of the herb’s actions in inflammatory diseases.
Propolis
Propolis is a resinous substance derived from poplar andconifer buds and used by Apis mellifera bees for maintaining theirhives. The pharmacologically active molecules in propolis areflavonoids and phenolic acids and their esters. These componentshave proven antibiotic effects on bacteria, fungi, and viruses.21
New evidence suggests that propolis may suppress the lipoxygenasepathway thereby decreasing PG and LT synthesis.22 Instudies using the rat paw edema model, it has been theorizedthat caffeic acid phenethyl ester (CAPE) is the constituent that ismost responsible for the anti-inflammatory effects of propolis forreducing acute and chronic inflammation.23
One study investigated the effects of both CAPE and galangin(an ethanolic extract of propolis) on cyclo-oxygenase (COX)activity. Propolis inhibited COX activity significantly in a dosedependentmanner. Similar results were obtained independentlywith CAPE and galangin; however, the COX inhibitory effectof propolis containing galangin but not CAPE, was determined to be approximately 10 times less potent than the extract containingCAPE. Both CAPE and galangin contribute to the activity of propolis, although CAPE is the stronger - actingconstituent.24
The anti-inflammatory effects of this plant medicine have alsobeen studied in other models of inflammation such as corneal injuryand skin burns. It was shown toproduce anti-inflammatory effectscomparable to dexamethasone intreating experimentally inducedchemical corneal injury.25 Propoliswas compared to silver sulfadiazine(SSD) for treating superficialsecond-degree burns. Burns treated with propolis had less inflammation and increased cicatrizationcompared to those treated with SSD, and no significant differencesin microbial-wound colonization were noted between thetwo treatment groups in one study.26 The researchers hypothesizedthat, had the dressing been changed more frequently (fewerthan every 3 days), the antimicrobial and healing effects mayhave been enhanced.
The two previous studies exemplify the broad use of propolisas an anti-inflammatory agent that can be useful for treating anumber of conditions with various medical therapies, many ofwhich may yet be discovered.
Boswellia
Boswellia (Boswellia serrata), also known as frankincense, isnative to the Indian continent, North Africa, and the Middle East,and is used widely as a traditional herb in Ayurvedic medicinefor treating inflammatory disease.
The resin, or gum, from the plant contains pentacyclic triterpenes(boswellic acids) of which produce much of this plant’santi-inflammatory activity. Nearly 16 percent of the resin iscomprised of essential oil. The acids contained in boswelliainhibit the enzyme 5-lipoxygenase by binding to the enzyme,resulting in decreased LT production in neutrophilic granulocytes.
Several clinical trials have attributed beneficial effects ofthis herb in treating chronic inflammatory diseases, such asrheumatoid arthritis , chronic colitis , ulcerative colitis,Crohn’ s disease, asthma, and tumor - associated brainedema.27
In a study of patients with colitis, a gum resin extract ofBoswellia serrata was supplied at a dose of 900 mg, three times perday, for 6 weeks while a control group was maintained on 3 g perday of sulfasalazine for 6 weeks. Ninety (90) percent of theboswellia-treated patients experienced improvements in stoolproperties; histopathology; and levels of hemoglobin, iron, calcium,phosphorus, proteins, and total leukocytes and eosinophils,with few side-effects, while 60 percent of the sulfasalazine-treatedpatients experienced similar results. However, fourteen (14) of the20 boswellia-treated patients experienced remissions, while only 4of the 10 sulfasalazine-treated patients reached remission.28
Boswellia has been proven to be effective for treating asthmaalso and the beneficial effects are attributed to LT inhibition. Seventy(70) percent of subjects who were treated with 300 mg of theherb, three times per day, for 6 weeks, experienced improvementsin forced expiratory volume 1 (FEV1), forced vital capacity (FVC),and peak expiratory flow rate (PEFR). What is more, these samesubjects had decreased eosinophiliccounts and erythrocyte sedimentationrates, plus subjective improvemen ts . The placebo groupexperienced a 27-percent improvementoverall.29
Boswellia serra ta can serve as apotent anti-inflammatory medicine and as a non-redox, noncompetitive specific inhibitor of the 5-lipoxygenase enzyme.
Conclusions
Science is continually discovering an inflammatory link in manychronic diseases, revealing this process as both a precipitive andpropagative factor in these conditions. Because of this new understanding,physicians must now, more than ever, use preventativemedicine to treat their patients.
Preventative anti-inflammatory treatments are numerous andmay be applied at various levels of care. The most motivatedpatients can alter the course of their health positively and preventchronic conditions, such as cardiovascular disease, cancer,Alzheimer’s disease, et cetera, simply by manipulating the fattyacidratios of their dietary intake.
In addition, patients with preexisting “chronic” disease conditionsmay also affect the outcomes of these disease processes byadhering to similar protocols. Natural medicines and nutritionalcofactors also collectively play an important role in preventingand treating diseases in which inflammation is active.
Greater understanding of these medicines and the benefits thatthey exert on various parts of the inflammatory process willallow practitioners use such natural anti-inflammatories safely totreat chronic inflammation as well as for general preventativehealth care.
References
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