n−3 Polyunsaturated fatty acids and inflammation: From molecular biology to the clinic

Lipids - Tập 38 - Trang 343-352 - 2003
Philip C. Calder1
1Institute of Human Nutrition, School of Medicine, University of Southampton, Southampton, UK

Tóm tắt

The immune system is involved in host defense against infectious agents, tumor cells, and environmental insults. Inflammation is an important component of the early immunologic response. Inappropriate or dysfunctional immune responses underlie acute and chronic inflammatory diseases. The n−6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds that have important roles in inflammation and in the regulation of immunity. Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators, through several mechanisms, including decreased availability of AA, competition for cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, and decreased expression of COX-2 and 5-LOX. This alone is a potentially beneficial anti-inflammatory effect of n−3 FA. However, n−3 FA have a number of other effects that might occur down-stream of altered eicosanoid production or might be independent of this effect. For example, dietary fish oil results in suppressed production of proinflammatory cytokines and can modulate adhesion molecule expression. These effects occur at the level of altered gene expression. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease and to protect against the effects of endotoxin. Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some asthmatics, supporting the idea that the n−3 FA in fish oil are anti-inflammatory. There are indications that the inclusion of fish oil in enteral and parenteral formulae is beneficial to patients.

Tài liệu tham khảo

Calder, P.C. (2001) Polyunsaturated Fatty Acids, Inflammation and Immunity, Lipids 36, 1007–1024. Stubbs, C.D., and Smith, A.D. (1984) The Modification of Mammalian Membrane Polyunsaturated Fatty Acid Composition in Relation to Membrane Fluidity and Function, Biochim. Biophys. Acta 779, 89–137. Murphy, M.G. (1990) Dietary Fatty Acids and Membrane Function, J. Nutr. Biochem. 1, 68–79. Grimble, R.F. (1998) Dietary Lipids and the Inflammatory Response, Proc. Nutr. Soc. 57, 535–542. Miles, E.A., and Calder, P.C. (1998) Modulation of Immune Function by Dietary Fatty Acids, Proc. Nutr. Soc. 57, 277–292. Gibney, M.J., and Hunter, B. (1993) The Effects of Short- and Long-Term Supplementation with Fish Oil on the Incorporation of n−3 Polyunsaturated Fatty Acids into Cells of the Immune System in Healthy Volunteers, Eur. J. Clin. Nutr. 47, 255–259. Sperling, R.I., Benincaso, A.I., Knoell, C.T., Larkin, J.K., Austen, K.F., and Robinson, D.R. (1993) Dietary ω-3 Polyunsaturated Fatty Acids Inhibit Phosphoinositide Formation and Chemotaxis in Neutrophils, J. Clin. Investig. 91, 651–660. Lewis, R.A., Austen, K.F., and Soberman, R.J. (1990) Leukotrienes and Other Products of the 5-Lipoxygenase Pathway: Biochemistry and Relation to Pathobiology in Human Diseases, N. Engl. J. Med. 323, 645–655. Tilley, S.L., Coffman, T.M., and Koller, B.H. (2001) Mixed Messages: Modulation of Inflammation and Immune Responses by Prostaglandins and Thromboxanes, J. Clin. Investig. 108, 15–23. Kinsella, J.E., Lokesh, B., Broughton, S., and Whelan, J. (1990) Dietary Polyunsaturated Fatty Acids and Eicosanoids: Potential Effects on the Modulation of Inflammatory and Immune Cells: An Overview, Nutrition 6, 24–44. Levy, B.D., Clish, C.B., Schmidt, B., Gronert, K., and Serhan, C.N. (2001) Lipid Mediator Class Switching During Acute Inflammation: Signals in Resolution, Nat. Immunol. 2, 612–619. Vachier, I., Chanez, P., Bonnans, C., Godard, P., Bousquet, J., and Chavis, C. (2002) Endogenous Anti-Inflammatory Mediators from Arachidonate in Human Neutrophils, Biochem. Biophys. Res. Commun. 290, 219–224. Gewirtz, A.T., Collier-Hyams, L.S., Young, A.N., Kucharzik, T., Guilford, W.J., Parkinson, J.F., Williams, I.R., Neish, A.S., and Madara, J.L. (2002) Lipoxin A4 Analogs Attenuate Induction of Intestinal Epithelial Proinflammatory Gene Expression and Reduce the Severity of Dextran Sodium Sulfate-Induced Colitis, J. Immunol. 168, 5260–5267. Obata, T., Nagakura, T., Masaki, T., Maekawa, K., and Yamashita, K. (1999) Eicosapentaenoic Acid Inhibits Prostaglandin D2 Generation by Inhibiting Cyclo-Oxygenase-2 in Cultured Human Mast Cells, Clin. Exp. Allergy 29, 1129–1135. Curtis, C.L., Hughes, C.E., Flannery, C.R., Little, C.B., Harwood, J.L., and Caterson, B. (2000) n−3 Fatty Acid Specifically Modulate Catabolic Factors Involved in Articular Cartilage Degradation, J. Biol. Chem. 275, 721–724. Curtis, C.L., Rees, S.G., Little, C.B., Flannery, C.R., Hughes, C.E., Wilson, C., Dent, C.M., Otterness, I.G., Harwood, J.L., and Caterson, B. (2002) Pathologic Indicators of Degradation and Inflammation in Human Osteoarthritic Cartilage Are Abrogated by Exposure to n−3 Fatty Acids, Arthritis Rheum. 46, 1544–1553. Endres, S., Ghorbani, R., Kelley, V.E., Georgilis, K., Lonnemann, G., van der Meer, J.M.W., Cannon, J.G., Rogers, T.S., Klempner, M.S., Weber, P.C., Schaeffer, E.J., Wolff, S.M., and Dinarello, C.A. (1989) The Effect of Dietary Supplementation with n−3 Polyunsaturated Fatty Acids on the Synthesis of Interleukin-1 and Tumor Necrosis Factor by Mononuclear Cells, N. Engl. J. Med. 320, 265–271. Meydani, S.N., Lichtenstein, A.H., Cornwall, S., Meydani, M., Goldin, B.R., Rasmussen, H., Dinarello, C.A., and Schaefer, E.J. (1993) Immunologic Effects of National Cholesterol Education Panel Step-2 Diets With and Without Fish-Derived n−3 Fatty Acid Enrichment, J. Clin. Invest. 92, 105–113. Caughey, G.E., Mantzioris, E., Gibson, R.A., Cleland, L.G., and James, M.J. (1996) The Effect on Human Tumor Necrosis Factor α and Interleukin 1β Production of Diets Enriched in n−3 Fatty Acids from Vegetable Oil or Fish Oil, Am. J. Clin. Nutr. 63, 116–122. Lee, T.H., Hoover, R.L., Williams, J.D., Sperling, R.I., Ravalese, J., Spur, B.W., Robinson, D.R., Corey, E.J., Lewis, R.A., and Austen, K.F. (1985) Effects of Dietary Enrichment with Eicosapentaenoic Acid and Docosahexaenoic Acid on in vitro Neutrophil and Monocyte Leukotriene Generation and Neutrophil Function, N. Engl. J. Med. 312, 1217–1224. Serhan, C.N., Clish, C.B., Brannon, J., Colgan, S.P., Gronert, K. and Chiang, N. (2000) Anti-Inflammatory Lipid Signals Generated From Dietary n−3 Fatty Acids via Cyclooxygenase-2 and Transcellular Processing: A Novel Mechanism for NSAID and n−3 PUFA Therapeutic Actions, J. Physiol. Pharmacol. 4, 643–654. Calder, P.C. (1997) n−3 Polyunsaturated Fatty Acids and Cytokine Production in Health and Disease, Ann. Nutr. Metab. 41, 203–234. de Caterina, R., Cybulsky, M.I., Clinton, S.K., Gimbrone, M.A., and Libby, P. (1994) The Omega-3 Fatty Acid Docosahexaenoate Reduces Cytokine-Induced Expression of Proatherogenic and Proinflammatory Proteins in Human Endothelial Cells, Arterioscler. Thromb. 14, 1829–1836. Khalfoun, B., Thibault, F., Watier, H., Bardos, P., and Lebranchu, Y. (1997) Docosahexaenoic and Eicosapentaenoic Acids Inhibit in vitro Human Endothelial Cell Production of Interleukin-6, Adv. Exp. Biol. Med. 400, 589–597. Chu, A.J., Walton, M.A., Prasad, J.K., and Seto, A. (1999) Blockade by Polyunsaturated n−3 Fatty Acids of Endotoxin-Induced Monocytic Tissue Factor Activation Is Mediated by the Depressed Receptor Expression in THP-1 Cells, J. Surg. Res. 87, 217–224. Billiar, T., Bankey, P., Svingen, B., Curran, R.D., West, M.A., Holman, R.T., Simmons, R.L., and Cerra, F.B. (1988) Fatty Acid Uptake and Kupffer Cell Function: Fish Oil Alters Eicosanoid and Monokine Production to Endotoxin Stimulation, Surgery 104, 343–349. Renier, G., Skamene, E., de Sanctis, J., and Radzioch, D. (1993) Dietary n−3 Polyunsaturated Fatty Acids Prevent the Development of Atherosclerotic Lesions in Mice: Modulation of Macrophage Secretory Activities, Arterioscler. Thomb. 13, 1515–1524. Yaqoob, P., and Calder, P.C. (1995) Effects of Dietary Lipid Manipulation upon Inflammatory Mediator Production by Murine Macrophages, Cell. Immunol. 163, 120–128. Sadeghi, S., Wallace, F.A., and Calder, P.C. (1999) Dietary Lipids Modify the Cytokine Response to Bacterial Lipopolysaccharide in Mice, Immunology 96, 404–410. Meydani, S.N., Endres, S., Woods, M.M., Goldin, B.R., Soo, C., Morrill-Labrode, A., Dinarello, C., and Gorbach, S.L. (1991) Oral (n−3) Fatty Acid Supplementation Suppresses Cytokine Production and Lymphocyte Proliferation: Comparison Between Young and Older Women, J. Nutr. 121, 547–555. Gallai, V., Sarchielli, P., Trequattrini, A., Franceschini, M., Floridi, A., Firenze, C., Alberti, A., Di Benedetto, D., and Stragliotto, E. (1993) Cytokine Secretions and Eicosanoid Production in the Peripheral Blood Mononuclear Cells of MS Patients Undergoing Dietary Supplementation with n−3 Polyunsaturated Fatty Acids, J. Neuroimmunol. 56, 143–153. Calder, P.C., Bond, J.A., Harvey, D.J., Gordon, S., and Newsholme, E.A. (1990) Uptake of Saturated and Unsaturated Fatty Acids into Macrophage Lipids and Their Effect upon Macrophage Adhesion and Phagocytosis, Biochem. J. 269, 807–814. Kim, D.N., Schmee, J., and Thomas, W.A. (1995) Dietary Fish Oil Added to a Hyperlipidemic Diet for Swine Results in Reduction in the Excessive Number of Monocytes Attached to the Arterial Endothelium, Atherosclerosis 81, 209–216. de Caterina, R., and Libby, P. (1996) Control of Endothelial Leukocyte Adhesion Molecules by Fatty Acid, Lipids 31, S57-S63. Hughes, D.A., Southon, S., and Pinder, A.C. (1996) (n−3) Polyunsaturated Fatty Acids Modulate the Expression of Functionally Associated Molecules on Human Monocytes in vitro, J. Nutr. 126, 603–610. Miles, E.A., Wallace, F.A., and Calder, P.C. (2000) Dietary Fish Oil Reduces Intercellular Adhesion Molecule 1 and Scavenger Receptor Expression on Murine Macrophages, Atherosclerosis 152, 43–50. Hughes, D.A., Pinder, A.C., Piper, Z., Johnson, I.T., and Lund, E.K. (1996) Fish Oil Supplementation Inhibits the Expression of Major Histocompatibility Complex Class II Molecules and Adhesion Molecules on Human Monocytes, Am. J. Clin. Nutr. 63, 267–272. Miles, E.A., Thies, F., Wallace, F.A., Powell, J.R., Hirst, T.L., Newsholme, E.A., and Calder, P.C. (2001) Influence of Age and Dietary Fish Oil on Plasma Soluble Adhesion Molecule Concentrations, Clin. Sci. 100, 91–100. Chandrasekar, B., and Fernandes, G. (1994) Decreased Proinflammatory Cytokines and Increased Antioxidant Enzyme Gene Expression by ω-3 Lipids in Murine Lupus Nephritis, Biochem. Biophys. Res. Commun. 200, 893–898. Robinson, D.R., Urakaze, M., Huang, R., Taki, H., Sugiyama, E., Knoell, C.T., Xu, L., Yeh, E.T.H., and Auron, P.E. (1996) Dietary Marine Lipids Suppress Continuous Expression of Interleukin-1β Gene Expression, Lipids 31, S23-S31. Christman, J.W., Lancaster, L.H., and Blackwell, T.S. (1998) Nuclear Factor-κB: A Pivotal Role in Systemic Inflammatory Response Syndrome and New Target for Therapy, Int. Care Med. 24, 1131–1138. Chen, F., Castranova, V., Shi, X., and Demers, L.M. (1999) New Insights into the Role of Nuclear Factor-κB, a Ubiquitous Transcription Factor in the Initiation of Diseases, Clin. Chem. 45, 7–17. Calder, P.C. (2002) Dietary Modification of Inflammation with Lipids, Proc. Nutr. Soc. 61, 345–358. Karin, M., and Ben-Neriah, Y. (2000) Phosphorylation Meets Ubiquination: The Control of NF-κB Activity, Annu. Rev. Immunol. 18, 621–663. Karin, M., and Delhase, M. (2000) The IκB Kinase (IκK) and NF-κB: Key Elements of Proinflammatory Signalling, Semin. Immunol. 12, 85–98. Xi, S., Cohen, D., Barve, S., and Chen, L.H. (2001) Fish Oil Suppressed Cytokines and Nuclear Factor κB Induced by Murine AIDS Virus Infection, Nutr. Res. 21, 865–878. Chen, L.H., and Zhao, Y. (2001) Eicosapentaenoic Acid Decreases Lipopolysaccharide-Stimulated Tumor Necrosis Factor-α Expression by Inhibiting Nuclear Factor κB Activation, FASEB J. 15, A258. Ross, J.A., Moses, A.G.W., and Fearon, K.C.H. (1999) The Anti-Catabolic Effects of n−3 Fatty Acids, Curr. Opin. Clin. Nutr. Metab. Care 2, 219–226. Schoonjans, K., Staels, B., and Auwerx, J. (1996) The Peroxisome Proliferator Activated Receptor (PPARs) and Their Effects on Lipid Metabolism and Adipocyte Differentiation, Biochim. Biophys. Acta 1302, 93–109. Chinetti, G., Griglio, S., Antonucci, M., Torra, I.P., Delerive, P., Majd, Z., Fruchart, J.C., Chapman, J., Najib, J., and Staels, B. (1998) Activation of Peroxisome-Activated Receptors α and γ Induces Apoptosis of Human Monocyte-Derived Macrophages, J. Biol. Chem. 273, 25573–25580. Ricote, M., Li, A.C., Wilson, T.M., Kelly, C.J., and Glass, C.K. (1998) The Peroxisome Proliferator-Activated Receptor-γ Is a Negative Regulator of Macrophage Activation, Nature 391, 79–82. Kleiwer, S.A., Lenhard, J.M., Willson, T.M., Patel, I., Morris, D.C., and Lehman, J.M. (1995) A Prostaglandin J2 Metabolite Binds Peroxisome Proliferator-Activated Receptor γ and Promotes Adipocyte Differentiation, Cell 83, 813–819. Devchand, P.R., Keller, H., Peters, J.M., Vazquez, M., Gonzalez, F.J., and Wahli, W. (1996) The PPARγ-Leukotriene B4 Pathway to Inflammation Control, Nature 384, 39–43. Jiang, C.Y., Ting, A.T., and Seed, B. (1998) PPAR-γ Agonists Inhibit Production of Monocyte Inflammatory Cytokines, Nature 391, 82–86. Poynter, M.E., and Daynes, R.A. (1998) Peroxisome Proliferator-Actived Receptor α Activation Modulates Cellular Redox Status, Represses Nuclear Factor κB Signalling, and Reduces Inflammatory Cytokine Production in Aging, J. Biol. Chem. 273, 32833–32841. Jackson, S.M., Parhami, F., Xi, X.-P., Berlinger, J.A., Hsueh, W.A., Law, R.E., and Demer, L.L. (1999) Peroxisome Proliferator-Activated Receptor Activators Target Human Endothelial Cells to Inhibit Leukocyte-Endothelial Cell Interaction, Arterioscler, Thromb. Vasc. Biol. 19, 2094–2104. Marx, N., Sukhova, G.K., Collins, T., Libby, P., and Plutzky, J. (1999) PPARα Activators Inhibit Cytokine-Induced Vascular Cell Adhesion Molecule-1 Expression in Human Endothelial Cells, Circulation 99, 3125–3131. Takano, H., Nagai, T., Asakawa, M., Toyozaki, T., Oka, T., Komuro, I., Saito, T., and Masuda, Y. (2000) Peroxisome Proliferator-Receptor Activators Inhibit Lipopolysaccharide-Induced Tumor Necrosis Factor-Alpha Expression in Neonatal Rat Cardiac Myocytes, Circ. Res. 87, 596–602. Wang, P., Anderson, P.O., Chen, S.W., Paulsson, K.M., Sjogren, H.O., and Li, S.L. (2001) Inhibition of the Transcription Factors AP-1 and NF-κB in CD4 T Cells by Peroxisome Proliferator-Activated Receptor γ Ligands, Int. Immunopharmacol. 1, 803–812. Xu, X., Otsuki, M., Saito, H., Sumitani, S., Yamamoto, H., Asanuma, N., Kouh, A.A., and Kasayama, S. (2001) PFARα and GR Differentially Down-Regulate the Expression of Nuclear Factor-κB-Responsive Genes in Vascular Endothelial Cells, Endocrinology 142, 3332–3339. Chinetti, G., Fruchart, J.C., and Staels, B. (2000) Peroxisome Proliferator-Activated Receptors (PPARs): Nuclear Receptors at the Crossroads Between Lipid Metabolism and Inflammation, Inflamm. Res. 49, 497–505. Delerive, P., Fruchart, J.C., and Staels, B. (2001) Peroxisome Proliferator-Activated Receptors in Inflammation Control, J. Endocrinol. 169, 453–459. Donnellan, C.E., Tadayyon, M., Briscoe, C., Arch, J., and Calder, P.C. (2000) The Effect of Dietary Fatty Acids on the Expression of Genes Involved in Lipid Handling, Proc. Nutr. Soc. 59, 111A (Abstr.). Hwang, D., and Rhee, S.H. (1999) Receptor-Mediated Signalling Pathways: Potential Targets of Modulation by Dietary Fatty Acids, Am. J. Clin. Nutr. 70, 545–556. Lo, C.J., Chiu, K.C., Fu, M.J., Chu, A., and Helton, S. (2000) Fish Oil Modulates Macrophages P44/42 Mitogen-Activated Protein Kinase Activity Induced by Lipopolysaccharide, J. Parenter. Enteral Nutr. 24, 159–163. Panayi, G.S. (1999) Targeting of Cells Involved in the Pathogenesis of Rheumatoid Arthritis, Rheumatology 38 (Suppl. 2), 8–10. Feldmann, M. and Maini, R.N. (1999) The Role of Cytokines in the Pathogenesis of Rheumatoid Arthritis, Rheumatology 38 (Suppl. 2), 3–7. Feldmann, M., Brennan, F.M., and Maini, R.N. (1996) Role of Cytokines in Rheumatoid Arthritis, Annu. Rev. Immunol. 14, 397–440. Sano, H., Hla, T., Maier, J.A.M., Crofford, L.J., Case, J.P., Maciag, T., and Wilder, R.L. (1992) In vivo Cyclooxygenase Expression in Synovial Tissues of Patients with Rheumatoid Arthritis and Osteoarthritis and Rats with Adjuvant and Streptococcal Cell Wall Arthritis, J. Clin. Investig. 89, 97–108. Sperling, R.I. (1995) Eicosanoids in Rheumatoid Arthritis, Rheum. Dis. Clin. N. Am. 21, 741–758. Faull, R.J. (1995) Adhesion Molecules in Health and Disease, Aust. N.Z.J. Med. 25, 720–730. Leslie, C.A., Gonnerman, W.A., Ullman, M.D., Hayes, K.C., Franzblau, C., and Cathcart, E.S. (1985) Dietary Fish Oil Modulates Macrophage Fatty Acids and Decreases Arthritis Susceptibility in Mice, J. Exp. Med. 162, 1336–1349. Volker, D.H., FitzGerald, P.E.B., and Garg, M.L. (2000) The Eicosapentaenoic to Docosahexaenoic Acid Ratio of Diets Affects the Pathogenesis of Arthritis in Lew/SSN Rats, J. Nutr. 130, 559–565. Calder, P.C. (2001) n−3 Fatty Acids and Rheumatoid Arthritis, in Food and Nutritional Supplements in Health and Disease (Ransley, J.K., Donnelly, J.K. and Read, N.W., eds.), pp. 175–197, Springer Verlag, London. Calder, P.C., and Zurier, R.B. (2001) Polyunsaturated Fatty Acids and Rheumatoid Arthritis, Curr. Opin. Clin. Nutr. Metab. Care 4, 115–121. Cleland, L.G., and James, M.J. (2000) Fish Oil and Rheumatoid Arthritis: Anti-Inflammatory and Collateral Health Benefits, J. Rheumatol. 27, 2305–2307. Knapp, H.R. (1995) Omega-3 Fatty-Acids in Respiratory Diseases—A Review, J. Am. Coll. Nutr. 14, 18–23. Calder, P.C., and Miles, E.A. (2000) Fatty Acids and Atopic Disease, Pediatr. Allergy Immunol. 11 (Suppl.), 29–36. Broughton, K.S., Johnson, C.S., Pace, B.K., Liebman, M., and Kleppinger, K.M. (1997) Reduced Asthma Symptoms with n−3 Fatty Acid Ingestion Are Related to 5-Series Leukotriene Production, Am. J. Clin. Nutr. 65, 1011–1017. Burney, P.G.J., Chinn, S., and Rona, R.J. (1990) Has the Prevalence of Asthma Increased in Children? Evidence from the National Survey of Health and Growth 1973–1986, Br. Med. J. 300, 1306–1310. Heinrich, J., Hoelscher, B., Frye, C., Meyer, I., Wjst, M., and Wichmann, H.E. (2002) Trends in Prevalence of Atopic Diseases and Allergic Sensitization in Children in Eastern Germany, Eur. Resp. J. 19, 1040–1046. Romagnani, S. (2000) The Role of Lymphocytes in Allergic Disease, J. Allergy Clin. Immunol. 105, 399–408. Hodge, L., Peat, J.K., and Salome, C. (1994) Increased Consumption of Polyunsaturated Oils May Be a Cause of Increased Prevalence of Childhood Asthma, Aust. N.Z. J. Med. 24, 727. Black, P.N., and Sharp, S. (1997) Dletary Fat and Asthma: Is There a Connection? Eur. Resp. J. 10, 6–12. Kankaanpaa, P., Sutas, Y., Salminen, S., Lichtenstein, A., and Isolauri, E. (1999) Dietary Fatty Acids and Allergy, Ann. Med. 31, 282–287. Yu, G., Kjellman, N.I., and Bjorksten, B. (1996) Phospholipid Fatty Acids in Cord Blood: Family History and Development of Allergy, Acta Paediatr. 85, 679–683. Duchen, K., Yu, G., and Bjorksten, B. (1998) Atopic Sensitization During the First Year of Life in Relation to Long-Chain Polyunsaturated Fatty Acid Levels in Human Milk, Pediatr. Res. 44, 478–484. Yu, G., and Bjorksten, B. (1998) Polyunsaturated Fatty Acids in School Children in Relation to Allergy and Serum IgE Levels, Pediatr. Allergy Immunol. 8, 133–138. Schwartz, J., and Weiss, S.T. (1994) The Relationship of Dietary Fish Intake to Level of Pulmonary Function in the First National Health and Nutrition Survey, Eur. Resp. J. 7, 1821–1824. Schwartz, J., and Weiss, S.T. (1990) Dietary Factors and Their Relation to Respiratory Symptoms: The Second National Health and Nutrition Survey, Am. J. Epidemiol. 132, 67–76. Hodge, L., Salome, C.M., Peat, J.K., Haby, M.M., Xuan, W., and Woodcock, A.J. (1996) Consumption of Oily Fish and Childhood Asthma Risk, Med. J. Aust. 164, 137–140. Dunder, T., Kuikka, L., Turtinen, J., Rasanen, L., and Uhari, M. (2001) Diet, Serum Fatty Acids, and Atopic Diseases in Childhood, Allergy 56, 425–428. Jones, A., Miles, E., Warner, J., Colwell, B., Bryant, T., and Warner, J. (1996) Fetal Peripheral Blood Mononuclear Cell Proliferative Responses to Mitogenic and Allergenic Stimuli During Gestation, Pediatr. Allergy Immunol. 7, 109–116. Cannon, J.G., Tompkins, R.G., Gelfrand, J.A., Michie, H.R., Stanford, G.G., Van der Meer, J.W., Endres, S., Lonnemann, G., Corsetti, J., Chernow, B., Wilmore, D.W., Wolff, S.M., Burke, J.F., and Dinarello, C.A. (1990) Circulating Interleukin-1 and Tumor Necrosis Factor in Septic Shock and Experimental Endotoxin Fever, J. Infect. Dis. 161, 79–84. Arnalich, F., Garcia-Palomero, E., Lopez, J., Jimenez, M., Madero, R., Renart, J., Vazquez, J.J., and Montiel, C. (2000) Predictive Value of Nuclear Factor κB Activity and Plasma Cytokine Levels in Patients with Sepsis, Infect. Immunol. 68, 1942–1945. Vervloet, M.G., Thijs, L.G., and Hack, C.E. (1998) Derangements of Coagulation and Fibrinolysis in Critically Ill Patients with Sepsis and Septic Shock, Semin. Thromb. Hemost. 24, 33–44. Grbic, J.T., Mannick, J.A., Gough, D.B., and Rodrick, M.L. (1991) The Role of Prostaglandin E2 in Immune Suppression Following Injury, Ann. Surg. 214, 253–263. Ertel, W., Morrison, M.H., Meldrum, D.R., Ayala, A., and Chaudry, I.H. (1992) Ibuprofen Restores Cellular Immunity and Decreases Susceptibility to Sepsis Following Hemorrhage, J. Surg. Res. 53, 55–61. Tashiro, T., Yamamori, H., Takagi, K., Hayashi, N., Furukawa, K., and Nakajima, N. (1998) n−3 Versus n−6 Polyunsaturated Fatty Acids in Critical Illness, Nutrition 14, 551–553. Hayashi, N., Tashiro, T., Yamamori, H., Takagi, K., Morishima, Y., Otsubo, Y., Sugiura, T., Furukawa, K., Nitta, H., Nakajima, N., Suzuki, N., and Ito, I. (1998) Effects of Intravenous Omega-3 and Omega-6 Fat Emulsion on Cytokine Production and Delayed Type Hypersensitivity in Burned Rats Receiving Total Parenteral Nutrition, J. Parenter. Enteral Nutr. 22, 363–367. Wachtler, P., Konig, W., Senkal, M., Kemen, M., and Koller, M. (1997) Influence of a Total Parenteral Nutrition Enriched with ω-3 Fatty Acids on Leukotriene Synthesis of Peripheral Leukocytes and Systemic Cytokine Levels in Patients with Major Surgery, J. Trauma 42, 191–198. Weiss, G., Meyer, F., Matthies, B., Pross, M., Koenig, W., and Lippert, H. (2002) Immunomodulation by Perioperative Administration of n−3 Fatty Acids, Br. J. Nutr. 87, S89-S94. Heyland, D.K., Novak, F., Drover, J.W., Jain, A., Su, X.Y., and Suchner, U. (2001) Should Immunonutrition Become Routine in Critically Ill Patients? A Systematic Review of the Evidence, J. Am. Med. Assoc. 286, 944–953. Braga, M., Vignali, A., Gianotti, L., Cestari, A., Profili, M., and Di Carlo, V. (1996) Immune and Nutritional Effects of Early Enteral Nutrition After Major Abdominal Operations, Eur. J. Surg. 162, 105–112. Braga, M., Gianotti, L., Radaelli, G., Vignali, A., Mari, G., Gentilini, O., and Di Carlo, V. (1999) Perioperative Immunonutrition in Patients Undergoing Cancer Surgery, Arch. Surg. 134, 428–433. Gianotti, L., Braga, M., Fortis, C., Soldini, L., Vignali, A., Colombo, S., Radaelli, G., and Di Carlo, V. (1999) A Prospective, Randomized Clinical Trial on Perioperative Feeding with an Arginine-, Omega-3 Fatty Acid-, and RNA-Enriched Enteral Diet: Effect on Host Response and Nutritional Status, J. Parenter. Enteral Nutr. 23, 314–320. Tepaske, R., and te Velthuis, H., Oudemans-van Straaten, M., Heisterkamp, S.H., van Deventer, S.J.H., Ince, C., Eysman, L., and Keseciogu, J. (2001) Effect of Preoperative Oral Immune-Enhancing Nutritional Supplement on Patients at Risk of Infection After Cardiac Surgery: A Randomised Placebo-Controlled Trial, Lancet 358, 696–701. Gadek, J.E., DeMichele, S.J., Karlstad, M.D., Pacht, E.R., Donahoe, M., Albertson, T.E., Van Hoozen, C., Wennberg, A.K., Nelson, J., Noursalehi, M., and the Enteral Nutrition in ARDS Study Group (1999) Effect of Enteral Feeding with Eicosapentaenoic Acid, γ-Linolenic Acid, and Antioxidants in Patients with Acute Respiratory Distress Syndrome, Crit. Care Med. 27, 1409–1420.