In the last three decades, the therapeutic utility of blocking lipid mediator generation in humans has become evident in a wide range of inflammatory disorders including asthma and arthritis. Animal studies have shown that certain diets, which alter the amount or types of fatty acid consumed, can reduce arachidonic acid (AA) metabolism and ameliorate several events associated with inflammation. However, dietary studies in humans have been less effective in both regards. After re-examining many of the previously-described dietary studies in humans utilizing well-defined diets (prepared and fed in a GCRC) and precise measurement techniques (GC/MS), we have found that in vivo supplementation of low to moderate fat diets with gammalinolenic acid (GLA) results in a marked decrease in the dihomogammalinolenic acid to AA ratio in neutrophil glycerolipids and a sharp reduction in the capacity of neutrophils to synthesize leukotrienes. These exciting findings support the central hypothesis of this proposal that specific dietary strategies (e.g., strategies which accumulate close structural analogs of AA in cellular glycerolipids) induce significant reductions in AA metabolism in human inflammatory cells resulting in anti- inflammatory effects. Specific aims: The aims of this proposal are designed to answer several key question within our central hypothesis: 1. What is the mechanism(s) leading to changes in fatty acids and AA metabolism after GLA supplementation?; 2. Do other (than the neutrophil) key inflammatory cells undergo similar changes in AA metabolism in response to dietary fatty acids?; 3. Can already-developed or newly- proposed strategies be used on a long term basis?; 4. Can these dietary strategies be utilized to treat inflammatory disorders such as asthma? Research design and methods: Negative ion chemical ionization GC/MS will provide very sensitive and selective assays for the measurements of polyunsaturated fatty acid and AA metabolites as well as a means to monitor the in vivo metabolism of fatty acids. The GCRC will provide precisely defined research meals to subjects in all dietary studies. Health relateness: Answering these fundamental questions will shed critical light on the feasibility of utilizing dietary fatty acids to regulate AA metabolism and related clinical disorders.

R01AI042022

1998-07-10

2003-05-31