EFFECTS OF EICOSAPENTAENOIC AND GAMMA-LINOLENIC ACID ON LUNG PERMEABILITY AND ALVEOLAR MACROPHAGE EICOSANOID SYNTHESIS IN ENDOTOXIC RATS

Objectives: Proinflammatory eicosanoids (cyclooxygenase and lipoxygena se metabolites of arachidonic acid) released by alveolar macrophages p lay an important role in endotoxin-induced acute lung injury. We inves tigated the effect of prefeeding rats for 21 days with enteral diets t hat provided the anti-inflammatory fatty acids, eicosapentaenoic acid and gamma-linolenic acid (derived from fish oil and borage oil, respec tively), as compared with an n-6 fatty acid-enriched diet (corn oil) o n the following: a) lung microvascular protein permeability, arterial blood pressure, and platelet and white blood cells in a model of endot oxin induced acute lung injury; b) alveolar macrophage prostaglandin a nd leukotriene syn thesis; and c) liver and alveolar macrophage phosph olipid fatty acid composition. Design: Prospective, randomized, contro lled, double-blind study. Setting: Research laboratory at a university medical center. Subjects: Male Long Evans rats, weighing 250 g. inter ventions: Rats were randomized into four dietary treatment groups and fed nutritionally complete diets (300 kcal/kg/day), containing 55.2% o f the total calories from fat with either 97% corn oil, 20% fish oil, 20% fish and 5% borage oil, or 20% fish and 20% borage oil for 21 days . On day 22, lung microvascular protein permeability, mean arterial pr essure, and platelet and white blood cell counts were determined for 2 hrs after an intravenous injection of Salmonella enteritidis endotoxi n (10 mg/kg). In a second group of prefed rats, the phospholipid fatty acid composition was determined in liver and alveolar macrophages. Al veolar macrophages were harvested by bronchoalveolar lavage and stimul ated in vitro with a calcium ionophore (A23187), and the concentration s of leukotrienes B-4 and B-5, thromboxane A(2), prostaglandin E(2), a nd 6-keto-prostaglandin F-1 alpha were measured in a third group of pr efed rats. Measurements and Main Results: Lung permeability was greate st with corn oil and was significantly attenuated with 20% fish oil an d 20% fish and 5% borage oil, and this effect approached significance with 20% fish and 20% borage oil (p=.06). The early and late hypotensi ve effects of endotoxin were attenuated with 20% fish oil, 20% fish an d 5% borage oil, and 20% fish and 20% borage oil, as compared with cor n oil. Concentrations of leukotriene B-4, prostaglandin E(2), and thro mboxane B-2 released from A23187-stimulated alveolar macrophages were significantly lower with 20% fish oil and 20% fish and 20% borage oil, as compared with corn oil. The increase in lung microvascular protein permeability with 20% fish and 20% borage oil was not significantly d ifferent than the lung microvascular protein permeability that was fou nd in animals receiving 20% fish oil (p=.20) and 20% fish and 5% borag e oil (p=.31). Alveolar macrophage and liver phospholipid concentratio ns of arachidonic acid were lower, and the concentrations of eicosapen taenoic acid and docosahexaenoic acid were higher, with 20% fish oil, 20% fish and 5% borage oil, and 20% fish and 20% borage oil, as compar ed with corn oil. Dihomo-gamma-linolenic acid, the desaturated and elo ngated intermediate of gamma-linolenic acid, was increased with 20% fi sh and 20% borage oil, as compared with 20% fish oil and 20% fish and 5% borage oil. Conclusions: The severity of pulmonary microvascular pr otein permeability and the degree of hypotension were reduced with fis h or fish and borage oil diets, as compared with corn oil, in endotoxi c rats. The reduced synthesis of the proinflammatory arachidonic acid derived mediators, leukotriene B-4, thromboxane B-2, and prostaglandin E(2) from stimulated alveolar macrophages was indicative of a decreas e in arachidonic acid and an increase in eicosapentaenoic acid and doc osahexaenoic acid in cell membrane phospholipids. The modulation of pr oinflammatory eicosanoid synthesis with anti-inflammatory fatty acids, eicosapentaenoic acid, and docosapentaenoic acid and gamma-linolenic acid, may have reduced the severity of pulmonary permeability and hypo tension after endotoxin administration.