Role of polyunsaturated fatty acids in lung disease.
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DF Horrobin hypothesized that the low prevalence of lung disease among Eskimos is the result of their diet, which is high in n-3 fatty acids. The n-3 and n-6 fatty acids shunt eicosanoid production away from the arachidonic acid pathway, and hence decrease the production of bronchoconstrictive leukotrienes. Animal studies showed that eicosapentaenoic acid or gamma-linolenic acid supplementation of animals exposed to endotoxins results in decreased effects on thromboxane B(2) and pulmonary vascular resistance. Small human trials confirmed that supplementation with eicosapentaenoic acid results in increased eicosapentaenoic acid in phospholipids and decreased generation of leukotrienes by neutrophils. Hence, a protective effect of such fatty acids in lung disease is biologically plausible. The results of human intervention studies looking at respiratory outcomes have been mixed, but they do suggest a possible difference between long-term and short-term effects. Epidemiologic studies showed possible protective effects against asthma in children, but weak to no evidence of such effects in adults. Results for bronchitis are more positive, although intervention trials are lacking. Recently, a cross-sectional analysis of data from the first National Health and Nutrition Examination Survey reported an approximately 80-mL difference in forced expiratory volume at 1 s between adults with high compared with low fish consumption. This response was not limited to asthmatic subjects. Others found that both fish consumption and n-3 fatty acid consumption (as estimated from food-frequency questionnaires) were protective against physician-diagnosed emphysema and chronic bronchitis and low spirometry values. Only smokers were included in this analysis. These results suggest that dietary fatty acids may play a role in lung disease; further work is needed to elucidate that role. (+info)
PAF-induced synthesis of tetraenoic and pentaenoic leukotrienes in the isolated rabbit lung.
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In an isolated rabbit lung model, we tested the hypothesis that platelet-activating factor (PAF)-induced leukotriene (LT) synthesis is critically dependent on the free precursor fatty acid supply and the possible substitution of arachidonic acid (AA) by eicosapentaenoic acid (EPA). To augment the intravascular polymorphonuclear neutrophils (PMNs) in the isolated lung, human PMNs were infused into the pulmonary artery. LTs and hydroxyeicosatetra(penta)enoic acids were quantified with HPLC techniques. Application of PAF (5 microM) or AA (10 microM) provoked the generation of limited quantities of 4-series LTs and 5-hydroxyeicosatetraenoic acid (total sum of 5-lipoxygenase products approximately 7 and approximately 27 pmol/ml in lungs both with and without infused PMNs, respectively). Combined administration amplified 5-lipoxygenase product formation, with a predominance of cysteinyl-LT synthesis in lungs both without (total sum approximately 67 pmol/ml) and, much more strikingly, with (total sum approximately 308 pmol/ml) an infusion of neutrophils. EPA (10 microM) elicited exclusive generation of 5-series LTs and 5-hydroxyeicosapentaenoic acid (total sum approximately 82 pmol/ml). Dual stimulation with PAF and EPA provoked amplification of EPA-derived 5-lipoxygenase product formation, again with predominance of cysteinyl-LTs in lungs without (total sum approximately 224 pmol/ml) and, in particular, with (total sum approximately 545 pmol/ml) preceding microvascular PMN entrapment. Combined application of PAF, AA, and EPA resulted in the synthesis of LTs derived from both fatty acids, with a predominance of 5-series products. We conclude that the PAF-evoked 5-lipoxygenase product formation in the neutrophil-harboring lung capillary bed is critically dependent on intravascular precursor fatty acid supply, with EPA representing the preferred substrate compared with AA. PMN-related transcellular eicosanoid synthesis is suggested to underlie the predominant generation of cysteinyl-LTs. The supply of n-3 versus n-6 precursor fatty acid may thus have a major impact on inflammatory mediator generation. (+info)
n-3 PUFA dietary supplementation inhibits proliferation and store-operated calcium influx in thymoma cells growing in Balb/c mice.
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The antitumor effect of daily individual administration of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (2 g/kg body weight) in Balb/c mice bearing a transplantable thymoma was investigated. Mice received oleic acid (control group), EPA and DHA ethyl esters starting 10 days before tumor inoculation. Analysis of phospholipid composition of neoplastic cell revealed that EPA and DHA levels were significantly increased (63 and 22% increase) after EPA and DHA treatments, respectively. Conversely, decreased levels of arachidonic acid were found in both cases (19 and 24% decrease in EPA and DHA groups, respectively). EPA and DHA delayed the appearance of macroscopic ascites (100% of animal, from 7 to 28 days), prolonged animal survival (100% of animal, from 22 to 32 and 33 days, respectively) and reduced the percentage of proliferating tumor cells detected by immunostaining of proliferation cell nuclear antigen (PCNA) (80 and 85% decrease, respectively). Moreover, the regulatory effects of these dietary n;-3 fatty acids on the influx of Ca(2+), activated by depletion of intracellular stores with thapsigargin (Tg), were investigated. By using a Ca(2+)-free/Ca(2+)-reintroduction protocol and Fura-2 as fluorescent indicator of intracellular free Ca(2+)([Ca(2+)](i)), we observed that EPA and DHA treatments markedly decreased Tg-induced rise in [Ca(2+)](i) (49 and 37% decrease, respectively). This effect was related to the inhibition of the store-operated Ca(2+) influx, as confirmed also by Mn(2+) influx experiments. The inhibitory action of EPA and DHA on the store-operated Ca(2+) influx could explain, at least in part, their antitumoral activity, as this Ca(2+) mobilization pathway appears to be involved in the cell signaling occurring in non-excitable cells to evoke many cellular processes, including cell proliferation. (+info)
Inhibition of sarcoplasmic reticulum function by polyunsaturated fatty acids in intact, isolated myocytes from rat ventricular muscle.
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1. We have studied the effects of two polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on spontaneous and electrically stimulated contractions in single, isolated ventricular myocytes from rat hearts. 2. The frequency of spontaneous waves of calcium release and contraction (induced by elevation of the bathing calcium concentration) is reduced in the presence of EPA. At the same time the resting level of intracellular calcium falls, the resting cell length increases and the amplitude of shortening decreases. All these effects are reversed on removal of EPA. 3. Imaging of the waves of calcium release shows that the amplitude and the rate of propagation of the wave is increased in EPA. Consistent with the increased amplitude, integration of the caffeine-induced Na+-Ca2+ exchange current (a measure of the sarcoplasmic reticulum (SR) calcium content) is increased by both EPA and DHA. 4. EPA has a maintained negative inotropic effect on voltage clamped myocytes. This seems to be entirely due to inhibition of the L-type calcium current. Smaller depolarising pulses in control conditions that elicit the same calcium current as in EPA also activate the same level of contraction. This is in spite of the increased SR calcium content in EPA. 5. It is concluded that PUFAs have two effects on the SR; they reduce the availability of calcium for uptake and they inhibit the release mechanism. Both of these effects should lower the frequency of spontaneous waves of calcium release. As spontaneous release of calcium can initiate arrhythmias, some of the anti-arrhythmic action of PUFAs must be exerted at the level of the SR. (+info)
The eicosapentaenoic to docosahexaenoic acid ratio of diets affects the pathogenesis of arthritis in Lew/SSN rats.
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Dietary-induced changes in tissue levels of polyunsaturated fatty acids modify inflammatory reactions through changes in the synthesis of lipid and peptide mediators of inflammation. Four semipurified 20% fat diets, based on beef tallow (BT), safflower oil (SFO), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were provided. The DHA and EPA ratios of the (n-3) fatty acid-based diets were 1.1 and 3.4, respectively. The effect of prefeeding diets differing in EPA to DHA ratios prior to the induction of streptococcal cell wall (SCW) arthritis in female Lew/SSN rats was examined. Weanling rats were fed diets for 5 wk before arthritis induction and 5 wk post-arthritis induction. Footpad thickness, hock circumference, plasma and macrophage fatty acids and histological assessment were compared. There were no differences in food intake and final body weights among the groups. Footpad inflammation, reported as percentage change (adjusted for growth) was greatest for rats fed the BT-based diet, intermediate in those fed the SFO-based diet and least for the rats fed the EPA- and DHA-based diets (P < 0.05). Macrophage phospholipids revealed cellular incorporation of EPA and DHA from the fish-oil based diets which modified lipid and peptide mediators of inflammation. Histological sections of rat hocks ranked by severity of arthritis-related changes suggested that the SFO- and EPA-based diets were more successful in ameliorating the destructive arthritic phase in hock joints than the BT- and DHA-based diets (P = 0.09) in this model of arthritis. The course of SCW-induced arthritis can be altered by diet-induced changes in macrophage fatty acid composition. The EPA-based diet is more effective in suppression of inflammation than the DHA-based diet. (+info)
Eicosapentaenoic acid suppresses PDGF-induced DNA synthesis in rat mesangial cells: involvement of thromboxane A2.
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BACKGROUND: The administration of eicosapentaenoic acid (EPA) derived from marine oils has been shown to suppress vascular myocyte, lymphocyte, keratinocyte, and mesangial cell proliferation in vitro, although the effects are variable and most reports provide fragmented insight into the mechanism(s) responsible for altering cell growth, particularly the relationship of membrane lipid remodeling to changes in cell proliferation. Thus, these studies were designed to elucidate the effects of mesangial cell membrane fatty acid remodeling (induced by EPA) on cell growth, and to define the relevance of changes in the synthesis of growth-modulating eicosanoids. METHODS: Mesangial cells were grown in RPMI and 17% fetal calf serum, and were subcultured and grown for 48 hours in 17% delipidated serum or delipidated serum supplemented with 0 to 50 micrograms/mL of EPA. Quiescent EPA-loaded and control mesangial cells were subjected to stimulation with 20 ng/mL of platelet-derived growth factor (PDGF) followed by measurement of 3H-thymidine incorporation and cell number. RESULTS: Mesangial cells remodeled with EPA exhibited a significant decrease in PDGF-stimulated 3H-thymidine incorporation and cell number associated with a reduction in thromboxane A2 (TXA2) in the media. Importantly, the phospholipid fatty acid composition of mesangial cells grown in media enriched with EPA revealed an increase in EPA (0.5 +/- 0.02% to 17.02 +/- 0.52%) coupled with a reciprocal decrease in the precursor for TXA2, arachidonic acid (18.9 +/- 3.17% to 3.55 +/- 0.30%). Blockade of TXA2 synthesis in mesangial cells treated with indomethacin (0.1 to 100 mumol/L) or the specific TXA2 synthase inhibitor, U-63557A (0.1 to 100 mumol/L), evoked a similar reduction in PDGF-stimulated proliferation and TXA2 synthesis. Coincubation of PDGF with the TXA2 mimetic, U-46619 (1 mumol/L), reversed the growth suppression induced by cell membrane remodeling. CONCLUSIONS: These studies suggest that changes in membrane fatty acid composition induced by EPA modulates PDGF-stimulated proliferation by engendering a change in PDGF-stimulated TXA2 synthesis. Furthermore, we conclude that TXA2 functions as a comitogen for PDGF-stimulated mesangial cell growth. (+info)
Uptake and activation of eicosapentaenoic acid are related to accumulation of triacylglycerol in Ramos cells dying from apoptosis.
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The present study investigates the mechanism behind induction of cell death by eicosapentaenoic acid (EPA) in leukemia cells. The PUFA-sensitive cell lines Raji and Ramos, which die by necrosis and apoptosis upon incubation with EPA respectively, had 2- to 3-fold higher uptake rate of EPA than the PUFA-resistant U-698 cell line. Furthermore, Ramos cells contained more lipid bodies and 3-fold more triacylglycerol than U-698 cells after 24 h incubation with 60 microm EPA. The mechanism behind the increased rate of EPA uptake in the PUFA-sensitive cell lines was examined by comparing the expression of 6 different fatty acid binding proteins (FABPs) and 3 acyl-CoA synthetases (ACSs) in U-698 and Ramos cells. Moreover, enzymatic activity of ACS and acyl-CoA:1,2-diacylglycerol acyltransferase (ADGAT) was investigated. The protein expression level of CD36 and p-FABPpm, the mRNA level of FABP, liver-FABP, heart-FABP, intestinal-FABP, ACS1, ACS2, and enzymatic ADGAT activity were similar in the two cell lines. However, an mRNA signal observed with a probe for ACS3 was 1.7 times higher in Ramos than in U-698 cells, and lysate from Ramos cells had a higher capacity to activate EPA to EPA-CoA than U-698 cell lysate. In conclusion, the present findings indicate that cellular uptake, activation and incorporation of EPA into lipids may be related to induction of cell death in leukemia cell lines. (+info)
Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men.
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BACKGROUND: Regular consumption of n-3 fatty acids of marine origin can improve serum lipids and reduce cardiovascular risk. OBJECTIVE: This study aimed to determine whether eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids have differential effects on serum lipids and lipoproteins, glucose, and insulin in humans. DESIGN: In a double-blind, placebo-controlled trial of parallel design, 59 overweight, nonsmoking, mildly hyperlipidemic men were randomly assigned to receive 4 g purified EPA, DHA, or olive oil (placebo) daily while continuing their usual diets for 6 wk. RESULTS: Fifty-six men aged 48.8 +/- 1.1 y completed the study. Relative to those in the olive oil group, triacylglycerols fell by 0.45 +/- 0.15 mmol/L ( approximately 20%; P = 0.003) in the DHA group and by 0.37 +/- 0.14 mmol/L ( approximately 18%; P = 0.012) in the EPA group. Neither EPA nor DHA had any effect on total cholesterol. LDL, HDL, and HDL(2) cholesterol were not affected significantly by EPA, but HDL(3) cholesterol decreased significantly (6.7%; P = 0.032). Although HDL cholesterol was not significantly increased by DHA (3. 1%), HDL(2) cholesterol increased by approximately 29% (P = 0.004). DHA increased LDL cholesterol by 8% (P = 0.019). Adjusted LDL particle size increased by 0.25 +/- 0.08 nm (P = 0.002) with DHA but not with EPA. EPA supplementation increased plasma and platelet phospholipid EPA but reduced DHA. DHA supplementation increased DHA and EPA in plasma and platelet phospholipids. Both EPA and DHA increased fasting insulin significantly. EPA, but not DHA, tended to increase fasting glucose, but not significantly so. CONCLUSIONS: EPA and DHA had differential effects on lipids, fatty acids, and glucose metabolism in overweight men with mild hyperlipidemia. (+info)