Dietary arachidonate in milk replacer triggers dual benefits of PGE_2 signaling in LPS-challenged piglet alveolar macrophages
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摘要
Background: Respiratory infections challenge the swine industry, despite common medicinal practices. The dual signaling nature of PGE_2(supporting both inflammation and resolution) makes it a potent regulator of immune cell function. Therefore, the use of dietary long chain n-6 PUFA to enhance PGE_2 effects merits investigation.Methods: Day-old pigs(n = 60) were allotted to one of three dietary groups for 21 d(n = 20/diet), and received either a control diet(CON, arachidonate = 0.5% of total fatty acids), an arachidonate(ARA)-enriched diet(LC n-6,ARA = 2.2%), or an eicosapentaenoic(EPA)-enriched diet(LC n-3, EPA = 3.0%). Alveolar macrophages and lung parenchymal tissue were collected for fatty acid analysis. Isolated alveolar macrophages were stimulated with LPS in situ for 24 h, and m RNA was isolated to assess markers associated with inflammation and eicosanoid production.Culture media were collected to assess PGE_2 secretion. Oxidative burst in macrophages was measured by: 1)oxygen consumption and extracellular acidification(via Seahorse), 2) cytoplasmic oxidation and 3) nitric oxide production following 4, 18, and 24 h of LPS stimulation.Results: Concentration of ARA(% of fatty acids, w/w) in macrophages from pigs fed LC n-6 was 86% higher than CON and 18% lower in pigs fed LC n-3(P < 0.01). Following LPS stimulation, abundance of COX-2 and TNF-α mRNA(P < 0.0001), and PGE_2 secretion(P < 0. 01) were higher in LC n-6 PAM vs. CON. However, ALOX5 abundance was1.6-fold lower than CON. Macrophages from CON and LC n-6 groups were 4-fold higher in ALOX12/15 abundance(P < 0.0001) compared to LC n-3. Oxygen consumption and extracellular acidification rates increased over 4 h following LPS stimulation(P < 0.05) regardless of treatment. Similarly, increases in cytoplasmic oxidation(P < 0.001)and nitric oxide production(P < 0.002) were observed after 18 h of LPS stimulation but were unaffected by diet.Conclusions: We infer that enriching diets with arachidonic acid may be an effective means to enhance a stronger innate immunologic response to respiratory challenges in neonatal pigs. However, further work is needed to examine long-term safety, clinical efficacy and economic viability.
Background: Respiratory infections challenge the swine industry, despite common medicinal practices. The dual signaling nature of PGE_2(supporting both inflammation and resolution) makes it a potent regulator of immune cell function. Therefore, the use of dietary long chain n-6 PUFA to enhance PGE_2 effects merits investigation.Methods: Day-old pigs(n = 60) were allotted to one of three dietary groups for 21 d(n = 20/diet), and received either a control diet(CON, arachidonate = 0.5% of total fatty acids), an arachidonate(ARA)-enriched diet(LC n-6,ARA = 2.2%), or an eicosapentaenoic(EPA)-enriched diet(LC n-3, EPA = 3.0%). Alveolar macrophages and lung parenchymal tissue were collected for fatty acid analysis. Isolated alveolar macrophages were stimulated with LPS in situ for 24 h, and m RNA was isolated to assess markers associated with inflammation and eicosanoid production.Culture media were collected to assess PGE_2 secretion. Oxidative burst in macrophages was measured by: 1)oxygen consumption and extracellular acidification(via Seahorse), 2) cytoplasmic oxidation and 3) nitric oxide production following 4, 18, and 24 h of LPS stimulation.Results: Concentration of ARA(% of fatty acids, w/w) in macrophages from pigs fed LC n-6 was 86% higher than CON and 18% lower in pigs fed LC n-3(P < 0.01). Following LPS stimulation, abundance of COX-2 and TNF-α mRNA(P < 0.0001), and PGE_2 secretion(P < 0. 01) were higher in LC n-6 PAM vs. CON. However, ALOX5 abundance was1.6-fold lower than CON. Macrophages from CON and LC n-6 groups were 4-fold higher in ALOX12/15 abundance(P < 0.0001) compared to LC n-3. Oxygen consumption and extracellular acidification rates increased over 4 h following LPS stimulation(P < 0.05) regardless of treatment. Similarly, increases in cytoplasmic oxidation(P < 0.001)and nitric oxide production(P < 0.002) were observed after 18 h of LPS stimulation but were unaffected by diet.Conclusions: We infer that enriching diets with arachidonic acid may be an effective means to enhance a stronger innate immunologic response to respiratory challenges in neonatal pigs. However, further work is needed to examine long-term safety, clinical efficacy and economic viability.
Background: Respiratory infections challenge the swine industry, despite common medicinal practices. The dual signaling nature of PGE_2(supporting both inflammation and resolution) makes it a potent regulator of immune cell function. Therefore, the use of dietary long chain n-6 PUFA to enhance PGE_2 effects merits investigation.Methods: Day-old pigs(n = 60) were allotted to one of three dietary groups for 21 d(n = 20/diet), and received either a control diet(CON, arachidonate = 0.5% of total fatty acids), an arachidonate(ARA)-enriched diet(LC n-6,ARA = 2.2%), or an eicosapentaenoic(EPA)-enriched diet(LC n-3, EPA = 3.0%). Alveolar macrophages and lung parenchymal tissue were collected for fatty acid analysis. Isolated alveolar macrophages were stimulated with LPS in situ for 24 h, and m RNA was isolated to assess markers associated with inflammation and eicosanoid production.Culture media were collected to assess PGE_2 secretion. Oxidative burst in macrophages was measured by: 1)oxygen consumption and extracellular acidification(via Seahorse), 2) cytoplasmic oxidation and 3) nitric oxide production following 4, 18, and 24 h of LPS stimulation.Results: Concentration of ARA(% of fatty acids, w/w) in macrophages from pigs fed LC n-6 was 86% higher than CON and 18% lower in pigs fed LC n-3(P < 0.01). Following LPS stimulation, abundance of COX-2 and TNF-α mRNA(P < 0.0001), and PGE_2 secretion(P < 0. 01) were higher in LC n-6 PAM vs. CON. However, ALOX5 abundance was1.6-fold lower than CON. Macrophages from CON and LC n-6 groups were 4-fold higher in ALOX12/15 abundance(P < 0.0001) compared to LC n-3. Oxygen consumption and extracellular acidification rates increased over 4 h following LPS stimulation(P < 0.05) regardless of treatment. Similarly, increases in cytoplasmic oxidation(P < 0.001)and nitric oxide production(P < 0.002) were observed after 18 h of LPS stimulation but were unaffected by diet.Conclusions: We infer that enriching diets with arachidonic acid may be an effective means to enhance a stronger innate immunologic response to respiratory challenges in neonatal pigs. However, further work is needed to examine long-term safety, clinical efficacy and economic viability.
引文
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3.Haesebrouck F,Pasmans F,Chiers K,Maes D,Ducatelle R,Decostere A.Efficacy of vaccines against bacterial diseases in swine:what can we expect?Vet Microbiol.2004;100:255-68.
4.Kelly D,Coutts AGP.Early nutrition and the development of immune function in the neonate.Proc Nutr Soc.2000;59(2):177-85.
5.Calder PC.The relationship between the fatty acid composition of immune cells and their function.Prostag,Leukotr Ess.2008;79:101-8.
6.Martins de Lima T,Gorj?o R,Hatanaka E,Cury-Boaventura M,Portioli Silva E,Procopio J,et al.Mechanisms by which fatty acids regulate leucocyte function.J Clin Sci.2007;113:65-77.
7.Oliveros LB,Videla AM,Gimenez MS.Effect of dietary fat saturation on lipid metabolism,arachidonic acid turnover and peritoneal macrophage oxidative stress in mice.Braz J Med Biol Res.2004;37:311-20.
8.Bagga D,Wang L,Farias-Eisner R,Glaspy JA,Reddy ST.Differential effects of prostaglandin derived fromω-6 andω-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion.Proc Natl Acad Sci.2003;100:1751-6.
9.Babcock TA,Novak T,Ong E,Jho DH,Helton WS,Espat NJ.Modulation of lipopolysaccharide-stimulated macrophage tumor necrosis factor-αproduction byω-3 fatty acid is associated with differential Cyclooxygenase-2 protein expression and is independent of Interleukin-10.J Surg Res.2002;107(1):135-9.https://doi.org/10.1006/jsre.2002.6498.
10.Lee TH,Hoover RL,Williams JD,Sperling RI,Ravalese J,Spur BW,et al.Effect of dietary enrichment with Eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function.N Engl J Med.1985;312:1217-24.
11.Botham KM,Mayes PA.Biosynthesis of Fatty Acids&Eicosanoids.In:Murray RK,Rodwell VW,Bender D,editors.Harper's illustrated biochemistry.New York:McGraw-Hill Professional Publishing;2009.p.193-204.
12.Serhan CN,Chiang N,Van Dyke TE.Resolving inflammation:dual antiinflammatory and pro-resolution lipid mediators.Nat Rev Immunol.2008;8:349-61.
13.Calder PC.Polyunsaturated fatty acids and inflammation.Prostag,Leukotr Ess.2006;75:197-202.
14.Kawahara K,Hohjoh H,Inazumi T,Tsuchiya S,Sugimoto Y.Prostaglandin E2-induced inflammation:relevance of prostaglandin E receptors.Biochim Biophys Acta.1851;2015:414-21.
15.Tang T,Scambler TE,Smallie T,Cunliffe HE,Ross EA,Rosner DR,et al.Macrophage responses to lipopolysaccharide are modulated by a feedback loop involving prostaglandin E2,dual specificity phosphatase 1 and tristetraprolin.Sci Rep.2017.https://doi.org/10.1038/s41598-017-04100-1.
16.Brezinski ME,Serhan CN.Selective incorporation of(15S)-hydroxyeicosatetraenoic acid in phosphatidylinositol of human neutrophils:agonist-induced deacylation and transformation of stored hydroxyeicosanoids.Proc Natl Acad Sci.1990;87:6248-52.
17.Norris PC,Gosselin D,Reichart D,Glass CK,Dennis EA.Phospholipase A2regulates eicosanoid class switching during inflammasome activation.Proc Natl Acad Sci.2014;111:12746-51.
18.Levy BD,Serhan CN.Resolution of acute inflammation in the lung.Annu Rev Physiol.2014;76:467-92.
19.Serhan CN,Sheppard KA.Lipoxin formation during human neutrophilplatelet interactions.Evidence for the transformation of leukotriene A4 by platelet 12-lipoxygenase in vitro.J Clin Invest.1990;85:772-80.
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