Eicosanoid Inflammatory Mediators (Leukotrienes and Prostaglandins) and Allergies

What are Eicosanoids?

Eicosanoids (a.k.a. icosanoids) are autocrine (influence or regulate cells that produce them) and paracrine (influence or regulate cells in close vicinity) chemical mediators that are synthesized on demand and not stored in cells. They are rapidly deactivated into inactive metabolites within seconds or minutes before entering the circulation.

Eicosanoids classification varies between authorities but one possible method is as follows:

Sequence of Events Involved in Eicosanoid Biosynthesis

Note: Enzymes involved are highlighted in green

Eicosanoids, Inflammation and Dietary Levels of Omega-3 and Omega-6

Eicosanoids are derived from the essential fatty acids omega-3 and omega-6 and play a notable role in inflammation, immunity and as central nervous system messengers. 

Eicosanoids derived from arachidonic acid (omega-6 family) are considered to be generally pro-inflammatory, whereas those from DGLA (also omega-6 family) or the omega-3 EPA, are typically less inflammatory, inactive or anti-inflammatory in nature.

Although both omega-3 and 6 are essential for good health, some scientists consider the disproportionate consumption of omega-6 rich foods observed in the Western diet (omega-3 and omega-6 balance) as a major contributor to various diseases including cardiovascular disease and inflammatory conditions such as arthritis. However, others believe that the importance of omega-6 is overshadowed by the significant beneficial impact made by having a diet rich in omega-3.

A diet rich in omega-3 may be beneficial because:

• Less arachidonic acid (from omega-6 family)  is available to produce pro-inflammatory omega-6 eicosanoids
• Any arachidonic acid present has to compete with higher levels of EPA (from omega-3 family) and as well as any DGLA, for access to the enzymes (cyclooxygenase and lipoxygenase) it requires to produce pro-inflammatory omega-6 eicosanoids.
• The pro-inflammatory omega-6 eicosanoids derived from arachidonic acid are counteracted by those derived from omega-3 EPA as well as those from DGLA.

What are Leukotrienes?

When the body is exposed to allergens, histamine and other inflammatory chemical mediators are produced. Leukotrienes play a significant role in inflammation because these inflammatory chemicals are three to four orders of magnitude (1,000-10,000) more potent and longer lasting than histamine (Hammarström 1983, Schmidt and Rabe 2000)

Leukotrienes are produced in white blood cells/leukocytes and other immune cells (mast cells), and similar to prostaglandins, they are synthesized from arachidonic acid (Hallstrand and Henderson 2010). Different enzymes determine whether prostaglandins (Cyclooxygenase/cyclooxygenase pathway) or leukotrienes (Lipoxygenases/lipoxygenase pathway) are produced (See above: Sequence of Events Involved in Eicosanoid Biosynthesis).

There are two families of leukotrienes  (Berger 1999) and these are primarily associated with:

• Conditions where inflammation is dependent on neutrophils e.g. cystic fibrosis, psoriasis.
• Cysteinyl leukotrienes: Bronchoconstriction in asthma induced by eosinophils and mast cells and they play a role in anaphylaxis.

Leukotrienes cause tightening (bronchoconstriction) and inflammation of the airways as well as the production of excessive mucus. They also increase vascular permeability (Dahlén et al 1981) and recruit white blood cell to areas of inflammation. Leukotrienes appear to be associated with various diseases involving inflammatory or immediate hypersensitivity reactions including allergy responses, allergic rhinitis, nasal allergies and autoallergenic diseases e.g. asthma, inflammatory bowel disease, lupus, psoriasis and rheumatoid arthritis. Furthermore, they may play a role in atherosclerosis, heart attacks, strokes and some types of cancer.

Medicines used to decrease the production and block the action of leukotrienes are called leukotriene antagonists or modifiers, and these can reduce allergy symptoms, airway inflammatory damage as well as play a role in preventing asthma. However, they are not suitable for treating an actual asthma attack.

From a natural allergy treatment perspective, the anti-inflammatory nature of the plant pigment Quercetin may help allergy sufferers through lowering leukotriene formation by blocking the enzymes lipoxygenase and phospholipase A2 that are involved in the lipoxygenase pathway.

What are Prostaglandins?

Prostaglandins are derived from essential fatty acids, namely omega-3 (EPA) and omega-6 (GLA via DGLA, and arachidonic acid) and are produced in all body cells except red blood cells. They are made ‘onsite’ and localized where and when required; although hormone-like, this contrasts with typical endocrine hormones that are produced in one location then transported in the bloodstream to work at some distant site. Prostaglandins are broken down by the body quickly which helps localize and control the impact they can have.

Prostaglandins are associated with tissue damage or infection and thereby injury and illness. As part of the healing process they promote tissue inflammation, fever and pain. The relationship between body condition and prostaglandin levels relates to prostaglandin synthesis from arachidonic acid and its dependency on the enzyme cyclooxygenase as shown below:

 Note: 3 versions of cyclooxygenase are currently known, although COX-3 function is at present unclear.

The interplay between different types of prostaglandins and the various receptors (10 currently known) they interact with throughout the body determines the resulting actions. Even though it may appear the various prostaglandins sometimes counteract each other, when viewed collectively, they play an important role in regulating and protecting the body by influencing every organ system e.g. blood vessel constriction and dilation (blood flow), electrolytes, lipolysis, muscle contraction, permeability.

Furthermore, prostaglandins are involved in the following:

• Female reproduction/ovulation and stimulating sperm formation and testosterone secretion.
• Lowering stomach acid production and blood pressure.
• Promoting blood clotting, cardiac circulation and nerve function, cortisol production, gastrointestinal mucus secretions, sodium retention and T-cells.

The pharmaceutical manipulation of prostaglandins can be used to medical advantage, although doing so involves a trade-off between benefits and side-effects. For example:

• When natural prostaglandin levels are too high, controlling them pharmaceutically can help tackle unwanted inflammation associated with various conditions e.g. arthritis or certain cancers. The interplay between non-steroidal anti-inflammatory (NSAIDs) medications and prostaglandins is noteworthy because it provides a glimpse of the dynamic interplay and impact prostaglandins have on the body. Classical NSAIDs (as opposed to newer NSAIDs that selectively inhibit COX-2), such as Aspirin or Ibuprofen, block all types of cyclooxygenase (COX) enzymes which reduces prostaglandin levels with the following outcome:

Conversely, increasing prostaglandin levels pharmaceutically may also prove beneficial in some situations e.g. treating stomach ulcers or inducing labor.