The end-product metabolism of arachidonic acid (AA), a component of cellular membranes, produces pro-inflammatory 2-series prostaglandins and 4-series leukotrienes, which are highly active mediators of inflammation. AA is derived from the phospholipids layer of immune-cell membranes via phospholipase A-2 in response to immunologic stimuli. The cysteinyl leukotrienes C4, D4, and E4 are important mediators in asthma and are modulators of cytokine function, and they have been implicated in the pathophysiology of asthma via multiple mechanisms such as bronchial smooth muscle, vessels, and mucus secretory cells, while leukotriene B4 promotes leukocyte chemotaxis and less-potent bronchoconstriction.31 Immune cells that drive the inflammatory process contain high proportions of the n-6 polyunsaturated fatty acid (PUFA) AA in relation to low amounts of n-3 PUFA; the two fatty acids are structurally and functionally distinct. The n-3 PUFAs eicosapentaenoic acid (EPA) and doc-osahexaenoic acid (DHA), found in high proportions in oily fish and fish oils, produce antiinflammatory activity and are indicated for preventing asthma symptoms throughout the medical literature. Supplementation with fish oil results in partial replacement of AA in inflammatory-cell membranes with EPA, resulting in decreased production of AA-derived inflammatory mediators. However, this response alone is not totally indicative of the beneficial anti-inflammatory effects of n-3 PUFAs. Both animal and human studies have indicated that other anti-inflammatory effects of n-3 PUFAs may occur downstream from cell-membrane composition alteration, such as suppressed production of pro-inflammatory cytokines and inhibited adhesion molecule expression occurring at the level of altered gene expression.32 In one study, dietary supplementation with fish oil for 10 months in 29 children with bronchial asthma resulted in decreased asthma symptom scores and response to an acetylcholine challenge in the treatment group with no changes in the control group.33 Subjects in the treatment group received fish-oil capsules that contained 84 mg of EPA and 36 mg of DHA. The daily dosages of EPA and DHA were, respectively, 17.0-26.8 and 7.3-11.5 mg per kg of body weight (-1), while control subjects received capsules containing 300 mg of olive oil. No side effects were noted. Studies on fish oil consumption have revealed decreased lymphocyte proliferation, T-cell mediated cytotoxicity, natural-killer cell activity, macrophage-mediated cytotoxicity, monocyte and neutrophil chemotaxis, major histocompatibility (class II expression) and antigen presentation, production of pro-inflammatory cytokines (ILs -1 and -6, tumor necrosis factor), and adhesion molecule expression.34 The studies described previously demonstrate the ability of fish oil supplementation to inhibit the inflammatory process of asthma. Based on these findings, one would expect to see decreased asthma symptomatology and improved lung function with addition of fish oils to the diet. The majority of studies do not indicate an optimal dose; however, most doses offish oils both EPA and DHA range from 500 mg to 3 g per day.
Coleus (Coleus forskohlii) is a member of the mint family that has been used traditionally on the Indian subcontinent for treating asthma. The active component of the plant, forskolin, has hypotensive and spasmolytic properties.35 Forskolin's mechanism of action involves its ability to activate the enzyme adenylate cyclase. This action increases the amount of cyclic adenosine monophosphate (cAMP) in cells, which produces various physiologic and biochemical effects, including inhibition of mast-cell degranulation and histamine release as well as relaxing smooth muscle.36 Some pharmaceutical approaches to asthma are designed to increase cAMP levels by using an agent that binds to receptors that stimulate adenylate cyclase (corticosteroids) and inhibits the enzyme phosphodiesterase, which is responsible for the breakdown of cAMP. One example is the methylxanthine-derived drug, theophylline, which has fallen out of favor as an asthma therapy because of its narrow therapeutic window. Forskolin's effects on cAMP result in bronchial dilatation and asthma symptom relief.37 In addition, forskolin may be of benefit to patients with allergic asthma because this compound's antiallergy qualities also include histamine release inhibition.38 Forskolin is poorly absorbed orally, and many studies use inhaled forskolin for asthma treatment.
Tylophora (Tylophora asthmatica), another botanical medicine that is native to India, has been shown to have anti-asthmatic, anti-inflammatory, and anti-anaphylactic properties.39 These effects have been attributed to the plant's alkaloid constituents, tylophorine and tylophor-inine.40 For one study, 110 patients with asthma were instructed to chew and swallow one tylophora leaf each day for one week. At the end of the week, 62% of the test subjects reported moderate to complete relief of symptomatology and experienced a continued reduction of symptoms for several weeks following the study.41 Another study revealed improvements in lung function and decreased nocturnal symptoms in patients with asthma, an effect that, again, persisted past the seven-day trial duration.42
The primary active constituents of butterbur (Petasites hybridus) are the sesquiterpene compounds, petasin, and isopetasin. Numerous studies have shown the efficacy of Butterbur in allergic rhinitis. These studies have shown that butterbur supplementation significantly reduced the levels of histamine and leukotrienes.43 A prospective open trial with 64 adults and 16 children with asthma evaluated the effects of butterbur supplementation for two months. In this study, the number, duration, and severity of asthma attacks decreased. Peak flow, forced expiratory volume (FEV1), and all measured symptoms also improved. In addition, more than 40% of patients using asthma medications at baseline reduced intake of these medications by the end of the study.44 In a randomized, crossover, placebo-controlled study, 16 atopic asthmatic patients on a constant dose of inhaled corticosteroids were supplemented with 25 mg butterbur twice daily for one week. Exhaled nitric oxide was significantly reduced and both serum eosinophil cationic protein and peripheral blood eosinophil count were also significantly suppressed.45
Quercetin is an abundant flavonoid used medicinally for its antioxidant and anti-inflammatory activity. Quercetin inhibits cyclooxygenase and lipooxygenase enzymes, as well as inflammatory mediators such as leukotrienes and prostaglandins.46 Quercetin also inhibits the release of histamine from mast cells and basophils.47 Mast cells induce production of proinflammatory cytokines with immune regulatory properties. One study examined the effect of quercetin on the expression of pro-inflammatory cytokines in a human mast-cell line. The results showed that quercetin decreased the gene expression and production of tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 suggesting that quercetin may be suitable for the treatment of mast-cell-derived allergic inflammatory diseases, such as asthma.48 In vitro, quercetin was shown to inhibit histamine released from rat peritoneal mast cells. Chemically induced histamine release was inhibited by 95% and immunologically induced histamine release was inhibited by 97%.49 Although direct evidence of quercetin in asthma patients is lacking, the potent antihistamine and anti-inflammatory activity makes it likely to benefit this condition.
Pycnogenol (Pinus pinaster), a trademarked pine bark extract, has anti-inflammatory and antioxidant activity. In a randomized, placebo-controlled, double-blind study involving 60 sub jects aged 6-18 years old, pycnogenol supplementation was evaluated in patients with mild to moderate asthma over a three-month period. The results showed that the group taking pycnogenol had significantly more improvement in pulmonary functions and asthma symptoms, was able to reduce or discontinue their use of rescue inhalers, and there was a significant reduction of urinary leukotrienes compared to the placebo.50 In another randomized, doubleblind, placebo-controlled crossover study, 26 patients with varying asthma severity were supplemented with 1 mg=lb per day (maximum 200 mg per day) pycnogenol. Almost all of the patients responded favorably to pycnogenol supplementation with no adverse effects reported. There was also as significant reduction in serum leukotrienes in the pycnogenol group compared with the placebo.51
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