Project 3- Mechanism of Leukotriene Inhibition by a Borage Seed Oil Emulsion

Project Leader: Floyd (Ski) Chilton, Ph.D.
Scott Hemby, Ph.D., Co-Investigator
Jonathan A. Arm, M.D., Co-Investigator
Priscilla Ivester - Research Coordinator
Kelly Weaver - predoctoral student

Objective
We and others have demonstrated that dietary fatty acids such as gammalinolenic acid (GLA) eicosapentaenoic acid (EPA) and stearidonic acid (SDA), which are available over-the-counter in dietary supplements, inhibit the production of mediators of inflammation including leukotriene generation, a proven approach to the management of asthma. The overall objective of project 3 of the Center Grant is to conduct systematic studies to evaluate the molecular mechanism by which these supplements inhibit inflammation. It is our hypothesis that the levels of circulating fatty acids control the quantity of inflammatory messengers produced within inflammatory cells that participate in inflammatory diseases. We believe a better understanding of how these supplements work will facilitate the development of more effective fatty acid-based therapies that inhibit inflammatory diseases in humans.

Specific Aims
A family of inflammatory messengers, known as leukotrienes, has been shown to contribute to the pathogenesis of several inflammatory diseases. The major goal of specific aim 1 is to elucidate in humans the mechanism by which dietary fatty acids found in borage and marine oil combinations inhibit inflammatory mediator production in general and leukotriene generation in particular. Initial studies are designed to determine the biochemical basis by which dietary fatty acids block leukotriene production. Additionally, our clinical trials in both asthmatic and control subjects suggest that dietary fatty acid manipulation potently blocks leukotriene production in some subjects but not in others. More specifically, those subjects that produce high levels of leukotrienes are the subjects that responded best to dietary fatty acid manipulation. Studies in the second part of specific aim 1 are focused at understanding the genetic basis why some individuals respond to dietary fatty acid and others do not.

In the near future, newly developed seed oils from plants such as Echium Plantagineum are likely to be the basis for a number of important therapeutic products. Studies in specific aim 2 are designed to determine whether this seed oil (containing stearidonic acid and GLA) can influence inflammatory mediator production including leukotriene generation in human subjects. Our preliminary data demonstrate that echium oil, provided to humans, markedly reduces serum triglycerides in hyper-triglyceridemic patients without adversely affecting circulating arachidonic acid levels (J. Nutrition, 2004 134: 1406-1411). These studies raise critical questions of whether this promising botanical oil can inhibit the production of inflammatory mediators including leukotrienes in humans and thereby be developed as an anti-inflammatory therapeutic.