Asthma and related diseases

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Eicosanoids synthesized from arachidonic acid have a role in allergic diseases: PGD2, LTC4, LTD4 and LTE4 are produced by the cells that mediate pulmonary inflammation in asthma, such as mast cells, and are believed to be the major mediators of asthmatic bronchoconstriction (Fig. 4.10). Although its action as a precursor to leucotrienes has highlighted the significance of arachidonic acid in the aetiology of allergic disease, a second link with this fatty acid has been made. This is because PGE2 regulates the activities of lymphocytes. Of particular relevance in the context of allergic disease is the ability of PGE2 to inhibit the production of the Th1-type cytokines IL-2 and IFN-7 without affecting the production of the Th2-type cytokines IL-4 and IL-5, and to stimulate B-cells to produce IgE (Fig. 4.10). These observations suggest that PGE2 promotes the development of allergic disease. Since n-3 fatty acids potentially antagonize the effects of arachidonic acid, there may be a role for fish oil in treating, or in protecting against the development of, allergic diseases, including asthma. Hence, a number of trials of fish oil in asthma have been performed. Although some of these trials show fish oil-induced changes in production of some inflammatory mediators (e.g. LTB4), a number report no effects on clinical outcomes (e.g. Arm et al., 1988, 1989; see Calder and Miles, 2000). In con-

Table 4.3. Summary of clinical trials of n-3 polyunsaturated fatty acids in human chronic inflammatory diseases.

Disease

Number of double-blind, placebo-controlled studies

Doses of EPA + DHA used

Duration (weeks)

Key findings

Reviews

Rheumatoid arthritis

Crohn's disease

Ulcerative colitis

12-52

12-52

Psoriasis

1-6.4 12-52 All studies reported improvements, including reduced duration of morning stiffness, reduced number of tender or swollen joints, reduced joint pain, reduced time to fatigue and increased grip strength Twelve studies reported improvement in at least two clinical measures, and four studies reported improvement in at least four clinical measures Ten studies reported decreased joint tenderness Three studies reported significant decrease in the use of non-steroidal anti-inflammatory drugs Two studies reported no benefit One study reported a significant decrease in relapses One other study, which used oily fish (100-250 g day-1 for 2 years), reported a significant decrease in relapses One study reported no benefit (this study used the lowest dose of EPA plus DHA) One study reported a non-significant decrease in disease activity and a significant decrease in use of corticosteroids

Two studies reported benefit, including improved histological appearance of the colon, decreased disease activity, weight gain and decreased use of prednisolone Two other 'open' studies reported improved symptoms, improved histological appearance of the rectal mucosa and decreased use of prednisolone 1.8 8-12 One study reported significant improvement in itching, scaling and erythema One study reported no benefit

Three open studies (providing 10-18 g EPA+ DHA day-1 for 6-8 weeks) reported mild to moderate (two studies) or moderate to excellent (one study) improvements in scaling, itching, lesion thickness and erythema in the majority of patients

One open study that combined fish oil with a low-fat diet reported improvements

Volker and Garg (1996); James and Cleland (1997); Geusens (1998); Calder (2001d); Calder and Zurier

Belluzzi and Miglio (1998)

Rodgers (1998)

Ziboh (1998)

Raw264 Pge2 Prednisolone
  1. 4.10. Putative role of arachidonic acid in atopic disease. PGE2 inhibits production of the Th1-type cytokine, IFN-7, so allowing the production of Th2-type cytokines (e.g. IL-4) to proceed without inhibition. IL-4 promotes Ig class switching in B-cells to produce IgE; PGE2 also directly promotes IgE production by B-cells. Thus, PGE2 acts to promote the Th2-type response and IgE production. The 4-series LT (and some 2-series PG, such as PGD2) are the direct mediators of allergic inflammation. HETE, hydroxyeicosatetraenoic acid; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LT, leucotriene; PG, prostaglandin; Th, T-helper.
  2. 4.10. Putative role of arachidonic acid in atopic disease. PGE2 inhibits production of the Th1-type cytokine, IFN-7, so allowing the production of Th2-type cytokines (e.g. IL-4) to proceed without inhibition. IL-4 promotes Ig class switching in B-cells to produce IgE; PGE2 also directly promotes IgE production by B-cells. Thus, PGE2 acts to promote the Th2-type response and IgE production. The 4-series LT (and some 2-series PG, such as PGD2) are the direct mediators of allergic inflammation. HETE, hydroxyeicosatetraenoic acid; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LT, leucotriene; PG, prostaglandin; Th, T-helper.

trast, some studies have shown significant clinical improvements in patients (e.g. Dry and Vincent, 1991) and there are suggestions that this type of approach may be useful in conjunction with other drug- and diet-based therapies (see Calder and Miles, 2000). Broughton et al. (1997) compared the effects of low-dose and high-dose fish oil in adult atopic asthmatics; the actual amount of fish oil each patient consumed was calculated according to their regular n-6 PUFA intake, such that the ratio of n-6 to n-3 fatty acid in the diet was 10:1 (low fish oil) or 2:1 (high fish oil). At baseline and after each treatment period (i.e. with low and then high fish oil), lung function was measured in response to increasing doses of methacholine. With low n-3 fatty acid ingestion, methacholine-induced respiratory distress increased. In contrast, high n-3 fatty acid ingestion resulted in improved lung function in more than 40% of subjects; all measures of respiratory function were improved in this group of patients, who also showed a markedly elevated appearance of the EPA-derived 5-series LT in their urine. However, some patients did not respond to the high n-3 polyunsaturated fatty acid intake, which in some cases worsened respiratory function. This study suggests that there may be asthmatic subjects who respond positively to fish oil intervention but others whose response may be worsened by such a dietary intervention. Thus, this therapy should be approached cautiously until more is known about the factors that determine sensitivity to n-3 PUFAs.

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