Project 4- Treatment of Bronchial Asthma with Borage Seed Oil

Project Leader: Jonatham Arm, M.D.
Elliot Israel, M.D. - Co-Investigator
Lin Wang - Laboratory Technician

Asthma affects ~20 million Americans and results in annual direct and indirect health care costs of ~$8 billion.  Despite substantial improvements in our understanding of the epidemiology and pathobiology of asthma, its incidence has doubled in the last decade. Morbidity and mortality from the disease has risen proportionally and is especially prevalent among minority individuals.

There is a substantial body of evidence implicating a group of lipid mediators called leukotrienes in the pathogenesis of asthma. Leukotriene modifying drugs are now an established treatment for the disease.  These drugs fall into two categories; those that inhibit the generation of leukotrienes through inhibition of the enzyme, 5-lipoxygenase (5-LO), and those that antagonize the actions of the cysteinyl leukotrienes (Cys-LTs) at the type 1 receptor (CysLT1R).  Development of 5-lipoxygenase inhibitors was hampered by liver toxicity. The only drug to enter the market, Zileuton®, requires administration 4 times a day (leading to problems with compliance) and causes significant liver inflammation in ~4% of individuals.  While there are no studies that have directly compared the efficacy of 5-LO inhibitors with CysLT1R antagonists in the management of asthma, analysis of the available data suggest that 5-LO inhibition is the more effective approach.  Therefore, the availability of an effective, non-toxic, inhibitor of 5-LO that can be administered once or twice a day would be immensely beneficial.

Borage seed is rich in gamma linolenic acid (GLA).  Dietary supplementation with borage seed oil provides non-toxic effective inhibition of leukotriene generation. Mechamism-based studies suggest that these supplements have their effects by blocking 5-LO.  However, GLA also adversely increases circulating free arachidonic acid (AA), which has pro-inflammatory potential.  Supplementation of borage seed oil with the n-3 fatty acid, eicosapentaenoic acid (EPA), derived from fish-oil, prevents the conversion of GLA to AA by
5-desaturase, thereby preventing increases in circulating AA.  While EPA is an effective inhibitor of 5-desaturase, it is extracted from fish oil and is not well-tolerated due to its taste, smell and mouth-feel properties.  Furthermore, higher doses of EPA appear to blunt the effect of GLA as an inhibitor of leukotriene biosynthesis.  Stearidonic acid (SDA), is a metabolic precursor of EPA that is extracted from seed oils of botanical sources such as Echium Plantagineum.  Importantly, out laboratory has shown that humans convert this oil to EPA and yet it does not have the organoleptic properties of EPA.  This raises the exciting possibility that stearidonic acid in botanical oils may be a vegetable alternative for fish oil.  To test this hypothesis, we will;

Determine the optimal dose of SDA, in echium seed oil, that inhibits the rise in serum arachidonic acid when combined with GLA while maintaining effective inhibition of leukotriene generation in asthmatic individuals, and

Determine the efficacy of the optimal combination of GLA and SDA on the severity of mild to moderate persistent asthma.