gamma-linolenic-acid and Endotoxemia

Celecoxib, a selective cyclooxygenase-2 inhibitor, produces thrombotic events in patients predisposed to cardiovascular risk factors. One theory reported an increase in endothelial expression of tissue factor (TF) as a predisposing factor. This work explored the effect of evening primrose oil (EPO), a source of prostaglandin E1, and forskolin (a cyclic adenosine monophosphate stimulator) against the prothrombotic effect of celecoxib in mice. Lipopolysaccharide mouse model of endotoxemia was used to induce an upregulation of TF activity. Male mice received celecoxib (25 mg/kg), celecoxib plus EPO, or celecoxib plus forskolin for 4 weeks and then subjected to a prothrombotic challenge in the form of an intraperitoneal injection of lipopolysaccharide. Results showed an increase in plasma TF activity, endothelial TF expression, and thrombin-antithrombin (TAT) but lower antithrombin III (ATIII) level in mice that received celecoxib in comparison to those that received the vehicle. Adding EPO or forskolin to celecoxib regimen significantly decreased the prothrombotic effect of celecoxib. A positive correlation (r = 0.8501) was found between TF activity and TAT. Co-administration of EPO or forskolin decreased the activity of TF and mitigated the prothrombotic effect of celecoxib. Therefore, these combinations may have the utility to abrogate the prothrombotic adverse effect of celecoxib in clinical setting.

Topics: Animals; Antithrombin III; Blood Coagulation; Celecoxib; Colforsin; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Endotoxemia; Fibrinolytic Agents; gamma-Linolenic Acid; Linoleic Acids; Lipopolysaccharides; Lung; Male; Mice; Oenothera biennis; Peptide Hydrolases; Plant Oils; Thromboplastin; Thrombosis; Up-Regulation

To investigate whether a diet enriched with fish and borage oils, with their high polyunsaturated fatty acid (PUFA) content, alters surfactant composition and function during endotoxemia.. Prospective, randomized, blinded, controlled animal study.. Research laboratory at a medical center.. Thirty-six 15- to 25-kg, disease-free, castrated male pigs. DIETS AND MEASUREMENTS: Three groups of pigs (n = 12 per group) were fed for 8 days diets containing either omega-6 fatty acids (FAs) (corn oil; diet A), or omega-3 FAs (fish oil; diet B), or a combination of omega-6 and omega-3 FAs (borage and fish oils; diet C). Eight of 12 pigs in each group received a 0.1-mg/kg bolus of Escherichia coli endotoxin followed by a continuous infusion (0. 075 mg/kg/h). One lung was subsequently isolated ex vivo, and pressure-volume curves were measured. The contralateral lung was lavaged, and surfactant was analyzed for total and individual phospholipids and FA composition. Minimum and maximum surface tension was measured by bubble surfactometry.. Pigs fed either diet B or C had increased oleic acid (C(18:1) omega-9), eicosapentaenoic acid (EPA; C(20:5) omega-3), docosahexaenoic acid (C(22:6) omega-3), and total omega-3 and monounsaturated FAs in their surfactant PUFA pools. The relative percentage of linoleic acid (C(18:2) omega-6) and total omega-6 FAs were significantly lower from pigs fed diets B and C compared with diet A. Palmitic acid (C(16:0)) concentrations, the primary FA in surfactant, had a tendency to be lower in pigs fed diets B and C. There were no demonstrable effects on surfactant function or pulmonary compliance.. Diets containing EPA or EPA and gamma-linolenic acid altered the PUFA composition of pulmonary surfactant, but without demonstrable effects on surfactant function during porcine endotoxemia.

Topics: Animals; Dietary Fats; Eicosapentaenoic Acid; Endotoxemia; Enteral Nutrition; Fatty Acids, Unsaturated; gamma-Linolenic Acid; Lung; Lung Compliance; Male; Pulmonary Surfactants; Swine

Short-term (i.e., 3 d) continuous enteral feeding of diets containing eicosapentaenoic (EPA) and gamma-linolenic (GLA) polyunsaturated fatty acids (PUFA) to endotoxemic rats reduces the levels of arachidonic acid (AA) and linoleic acid (LA) in alveolar macrophage (AM) and liver Kupffer and endothelial (K&E) cell phospholipids with attendant decreases in prostaglandin formation by these cells in vitro. Diets that contain alpha-linolenic acid (LNA) as a substrate for endogenous formation of EPA may not be as effective in facilitating these immune cell modifications given the limited activity of delta6 desaturase. In the present study we compared the effectiveness of an LNA-enriched diet vs. an (EPA + GLA)-enriched diet to displace phospholipid AA from AM and liver K&E cells in vivo in endotoxemic rats fed enterally for 3 or 6 d. We determined the fatty acid composition of AM and K&E cell phospholipids by gas chromatography. We found that AM and K&E cells from rats that had received the EPA + GLA diet for 3 d had significantly (P < 0.001) higher mole percentage of EPA and the GLA metabolite, dihomoGLA, than corresponding cells from rats given the LNA diet or a control diet enriched with LA. Rats given the LNA diet had relatively low levels of stearidonic acid, EPA and other n-3 PUFA, while rats given the LA diet had low levels of GLA and dihomoGLA. We conclude that diets enriched with LNA or LA may not be as effective as those enriched with EPA + GLA for purposes of fostering incorporation of EPA or dihomoGLA into and displacement of AA from macrophage phospholipids under pathophysiologic conditions commonly found in acutely septic patients.

Topics: alpha-Linolenic Acid; Animals; Arachidonic Acid; Dietary Fats, Unsaturated; Eicosapentaenoic Acid; Endothelium; Endotoxemia; gamma-Linolenic Acid; Immune System; Kupffer Cells; Linoleic Acid; Liver; Lung; Macrophages, Alveolar; Male; Rats; Rats, Sprague-Dawley

Proinflammatory eicosanoids (cyclooxgenase and lipoxygenase metabolites of arachidonic acid) released by alveolar macrophages play an important role in endotoxin-induced acute lung injury. We investigated the effect of prefeeding rats for 21 days with enteral diets that provided the anti-inflammatory fatty acids, eicosapentaenoic acid and gamma-linolenic acid (derived from fish oil and borage oil, respectively), as compared with an n-6 fatty acid-enriched diet (corn oil) on the following: a) lung microvascular protein permeability, arterial blood pressure, and platelet and white blood cells in a model of endotoxin-induced acute lung injury; b) alveolar macrophage prostaglandin and leukotriene synthesis; and c) liver and alveolar macrophage phospholipid fatty acid composition.. Prospective, randomized, controlled, double-blind study.. Research laboratory at a university medical center.. Male Long-Evans rats, weighing 250 g.. Rats were randomized into four dietary treatment groups and fed nutritionally complete diets (300 kcal/kg/day), containing 55.2% of 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 pressure, and platelet and white blood cell counts were determined for 2 hrs after an intravenous injection of Salmonella enteritidis endotoxin (10 mg/kg). In a second group of prefed rats, the phospholipid fatty acid composition was determined in liver and alveolar macrophages. Alveolar macrophages were harvested by bronchoalveolar lavage and stimulated in vitro with a calcium ionophore (A23187), and the concentrations of leukotrienes B4 and B5, thromboxane A2, prostaglandin E2, and 6-keto-prostaglandin F1 alpha were measured in a third group of prefed rats.. Lung permeability was greatest with corn oil and was significantly attenuated with 20% fish oil and 20% fish and 5% borage oil, and this effect approached significance with 20% fish and 20% borage oil (p = .06). The early and late hypotensive effects of endotoxin were attenuated with 20% fish oil, 20% fish and 5% borage oil, and 20% fish and 20% borage oil, as compared with corn oil. Concentrations of leukotriene B4, prostaglandin E2, and thromboxane B2 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 different than the lung microvascular protein permeability that was found in animals receiving 20% fish oil (p = .20) and 20% fish and 5% borage oil (p = .31). Alveolar macrophage and liver phospholipid concentrations of arachidonic acid were lower, and the concentrations of eicosapentaenoic acid and docosahexaenic acid were higher, with 20% fish oil, and 5% borage oil, and 20% fish and 20% borage oil, as compared with corn oil. Dihomo-gamma-linolenic acid, the desaturated and elongated intermediate of gamma-linolenic acid, was increased with 20% fish and 20% borage oil, as compared with 20% fish oil and 20% fish and 5% borage oil.. The severity of pulmonary microvascular protein permeability and the degree of hypotension were reduced with fish or fish and borage oil diets, as compared with corn oil, in endotoxic rats. The reduced synthesis of the proinflammatory arachidonic acid-derived mediators, leukotriene B4, thromboxane B2, and prostaglandin E2 from stimulated alveolar macrophages was indicative of a decrease in arachidonic acid and an increase in eicosapentaenoic acid and docosahexaenoic acid in cell membrane phospholipids.

Topics: Animals; Capillary Permeability; Disease Models, Animal; Double-Blind Method; Drug Evaluation, Preclinical; Eicosapentaenoic Acid; Endotoxemia; gamma-Linolenic Acid; Lung; Macrophages, Alveolar; Male; Random Allocation; Rats; Rats, Inbred Strains; Respiratory Distress Syndrome

Proinflammatory eicosanoids and cytokines are important mediators of local inflammation in acute lung injury. We determined if enteral nutrition with anti-inflammatory fatty acids, eicosapentaenoic acid, and gamma-linolenic acid would reduce the intrapulmonary synthesis of proinflammatory eicosanoids and cytokines and pulmonary neutrophil accumulation in a rat model of acute lung injury.. Prospective, randomized, controlled, double-blind study.. Research laboratory at a university medical center.. Male Long-Evans rats (250 g).. Rats were randomly assigned to three dietary treatment groups and fed nutritionally complete diets (300 kcal/kg/day) containing 55.2% of the total calories from fat with either 97% corn oil, 20% fish oil, or 20% fish and 20% borage oil for 21 days. On day 22, bronchoalveolar lavage was performed 2 hrs after an intravenous injection of Salmonella enteritidis endotoxin (10 mg/kg) or saline. Bronchoalveolar lavage fluid was analyzed for leukotriene B4, leukotriene C4/D4, thromboxane B2, prostaglandin E2, 6 keto-prostaglandin F1alpha, tumor necrosis factor (TNF)-alpha, and macrophage inflammatory protein-2 (MIP-2). Lung myeloperoxidase activity (a marker for neutrophil accumulation) and phospholipid fatty acid composition were also determined.. Lung phospholipid concentrations of arachidonic acid were lower and the concentrations of eicosapentaenoic acid and docosahexaenoic acid were higher with fish oil and fish and borage oil as compared with corn oil. Dihomo-gamma-linolenic acid, the desaturated and elongated intermediate of gamma-linolenic acid, increased with fish and borage oil as compared with fish oil and corn oil. The levels of leukotriene B4, leukotriene C4/D4, 6-keto-prostaglandin F1alpha, and thromboxane B2 with corn oil were significantly increased with endotoxin as compared with saline. In contrast to the corn oil group, endotoxin did not significantly increase bronchoalveolar lavage levels of leukotriene B4, leukotriene C4/D4, and thromboxane B2 above those of saline-treated rats with fish oil and fish and borage oil. Lung myeloperoxidase activity was significantly increased in endotoxin-treated rats compared with those rats given saline in all dietary treatment groups. However, lung myeloperoxidase activity was significantly lower with either fish oil or fish and borage oil as compared with corn oil after endotoxin. Although endotoxin increased the levels of TNF-alpha and MIP-2 with all dietary treatment groups as compared with saline-treated rats, there were no significant differences in the levels of either cytokine between the dietary treatment groups.. These results indicate that dietary fish oil and fish and borage oil as compared with corn oil may ameliorate endotoxin-induced acute lung injury by suppressing the levels of proinflammatory eicosanoids (but not TNF-alpha or MIP-2) in bronchoalveolar lavage fluid and reducing pulmonary neutrophil accumulation.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cytokines; Dietary Fats, Unsaturated; Double-Blind Method; Eicosanoids; Eicosapentaenoic Acid; Endotoxemia; Evaluation Studies as Topic; Fish Oils; gamma-Linolenic Acid; Lung Diseases; Male; Neutrophils; Peroxidase; Phospholipids; Plant Oils; Prospective Studies; Random Allocation; Rats