Objectives:Because vasoactive eicosanoids derived from arachidonic acid present in immune cell phospholipids promote lung inflammation in critically ill patients, novel experimental diets containing eicosapentaenoic acid from fish oil and γ-linolenic acid from borage oil have been designed to limit arachidonic acid metabolism. However, excess dietary eicosapentaenoic acid impairs superoxide formation and bacterial killing by immune cells. The present study determined whether short-term enteral feeding with diets enriched with either eicosapentaenoic acid alone or in combination with γ-linolenic acid would modulate alveolar macrophage eicosanoid synthesis without compromising bactericidal function.Design:Prospective, randomized, controlled, blinded study.Setting:University medical center.Subjects:Adult male Sprague-Dawley rats.Interventions:Rats underwent surgical placement of a gastroduodenal feeding catheter and were randomly assigned to receive one of three high-fat (55.2% of total calories), low-carbohydrate diets containing isocaloric amounts of lipids for 4 days. The control diet was enriched with linoleic acid, whereas the two test diets were low in linoleic acid and enriched with either 5 mole % eicosapentaenoic acid alone or in combination with 5 mole % γ-linolenic acid. Alveolar macrophages were then procured to assess phospholipid fatty acid composition, eicosanoid synthesis after stimulation with endotoxin, superoxide formation and phagocytosis by flow cytometry, and killing ofStaphylococcus aureus.Measurements and Main Results:Alveolar macrophage levels of arachidonic acid were significantly (p< .01) lower and levels of eicosapentaenoic and dihomo-γ-linolenic acids were higher after feeding the eicosapentaenoic and γ-linolenic acid diet vs. the linoleic acid diet. Ratios of thromboxane B2,/B3, leukotriene B4/B5, and prostaglandin E2/E1were reduced in the macrophages from rats given either the eicosapentaenoic acid or eicosapentaenoic acid with γ-linolenic acid diet compared with ratios from rats given the linoleic acid diet. Macrophages from rats given the eicosapentaenoic with γ-linolenic acid diet released 35% or 24% more prostaglandin E1than macrophages from rats given either the linoleic acid or the eicosapentaenoic acid diet, respectively. Macrophage superoxide generation, phagocytosis of opsonized zymosan, and killing ofS. aureuswere similar irrespective of dietary treatment.Conclusion:Short-term enteral feeding with an eicosapentaenoic acid-enriched or eicosapentaenoic with γ-linolenic acid-enriched diet rapidly modulated the fatty acid composition of alveolar macrophage phospholipids, promoted a shift toward formation of less inflammatory eicosanoids by stimulated macrophages, but did not impair alveolar macrophage bactericidal function relative to responses observed after feeding a linoleic acid diet.