Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators (original) (raw)

• Majno, G. & Joris, I. Cells, Tissues, and Disease: Principles of General Pathology (Oxford Univ., New York, 2004).
  Google Scholar
• Weissmann, G., Smolen, J. E. & Korchak, H. M. Release of inflammatory mediators from stimulated neutrophils. N. Engl. J. Med. 303, 27–34 (1980).
  Article CAS PubMed Google Scholar
• Collard, C. D. & Gelman, S. Pathophysiology, clinical manifestations, and prevention of ischemia-reperfusion injury. Anesthesiology 94, 1133–1138 (2001).
  Article CAS PubMed Google Scholar
• Luster, A. D., Alon, R. & von Andrian, U. H. Immune cell migration in inflammation: present and future therapeutic targets. Nature Immunol. 6, 1182–1190 (2005).
  Article CAS Google Scholar
• Serhan, C. N. et al. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 21, 325–332 (2007). The first consensus report on the definitions and mechanisms of resolution.
  Article CAS PubMed Google Scholar
• Bannenberg, G. L. et al. Molecular circuits of resolution: formation and actions of resolvins and protectins. J. Immunol. 174, 4345–4355 (2005). This study reports the first in vivo molecular mapping of the formation and actions of protectins and resolvins using a new mediator lipidomics and proteomics systems approach.
  Article CAS PubMed Google Scholar
• Serhan, C. N. A search for endogenous mechanisms of anti-inflammation uncovers novel chemical mediators: missing links to resolution. Histochem. Cell Biol. 122, 305–321 (2004).
  Article CAS PubMed Google Scholar
• Levy, B. D., Clish, C. B., Schmidt, B., Gronert, K. & Serhan, C. N. Lipid mediator class switching during acute inflammation: signals in resolution. Nature Immunol. 2, 612–619 (2001).
  Article CAS Google Scholar
• Serhan, C. N. et al. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J. Exp. Med. 192, 1197–1204 (2000). This study identifies specialized lipid mediators in spontaneous resolution of inflammation, now known as resolvin E1.
  Article CAS PubMed PubMed Central Google Scholar
• Serhan, C. N. et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter pro-inflammation signals. J. Exp. Med. 196, 1025–1037 (2002). This reference reports the discovery of the resolvins in resolving exudates in vivo and describes the complete structure and bioactions of the D-series and E-series resolvins and protectins.
  Article CAS PubMed PubMed Central Google Scholar
• Hong, S., Gronert, K., Devchand, P., Moussignac, R.-L. & Serhan, C. N. Novel docosatrienes and 17_S_-resolvins generated from docosahexaenoic acid in murine brain, human blood and glial cells: autacoids in anti-inflammation. J. Biol. Chem. 278, 14677–14687 (2003). This study reports the identification of the DHA-derived anti-inflammatory resolvins and protectins.
  Article CAS PubMed Google Scholar
• Maddox, J. F. & Serhan, C. N. Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction. J. Exp. Med. 183, 137–146 (1996).
  Article CAS PubMed Google Scholar
• Gilroy, D. W., Lawrence, T., Perretti, M. & Rossi, A. G. Inflammatory resolution: new opportunities for drug discovery. Nature Rev. Drug Discov. 3, 401–416 (2004). A review emphasizing the potential of the resolution field for drug discovery.
  Article CAS Google Scholar
• Serhan, C. N., guest ed. Special Issue on Lipoxins and Aspirin-Triggered Lipoxins. Prostaglandins Leukot. Essent. Fatty Acids 73, 139–321 (2005). A collection of 19 reviews on the anti-inflammatory actions of lipoxins and aspirin-triggered lipoxins, and the therapeutic potential of stable metabolic analogues.
  Article CAS Google Scholar
• Schwab, J. M., Chiang, N., Arita, M. & Serhan, C. N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447, 869–874 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Canny, G. et al. Lipid mediator-induced expression of bactericidal/permeability-increasing protein (BPI) in human mucosal epithelia. Proc. Natl Acad. Sci. USA 99, 3902–3907 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Campbell, E. L. et al. Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution. FASEB J. 21, 3162–3170 (2007).
  Article CAS PubMed Google Scholar
• Flower, R. J. Prostaglandins, bioassay and inflammation. Br. J. Pharmacol. 147, S182–S192 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Samuelsson, B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 220, 568–575 (1983). A review on the biosynthesis and bioactions of leukotrienes.
  Article CAS PubMed Google Scholar
• Lands, W. E. M. Proceedings of the AOCS Short Course on Polyunsaturated Fatty Acids and Eicosanoids (American Oil Chemists' Society, Champaign, Illinois, 1987).
  Google Scholar
• Van Dyke, T. E. & Serhan, C. N. Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases. J. Dent. Res. 82, 82–90 (2003).
  Article CAS PubMed Google Scholar
• Kunkel, S. L., Ogawa, H., Conran, P. B., Ward, P. A. & Zurier, R. B. Suppression of acute and chronic inflammation by orally administered prostaglandins. Arthritis Rheum. 24, 1151–1158 (1981).
  Article CAS PubMed Google Scholar
• Hasturk, H. et al. Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo. J. Immunol. 179, 7021–7029 (2007). This reference reports the ability of resolvin E1 to stimulate bone regeneration.
  Article CAS PubMed Google Scholar
• Williams, T. J., Jose, P. J., Wedmore, C. V., Peck, M. J. & Forrest, M. J. Mechanisms underlying inflammatory edema: the importance of synergism between prostaglandins, leukotrienes, and complement-derived peptides. Adv. Prostaglandin Thromboxane Leukot. Res. 11, 33–37 (1983).
  Article CAS PubMed Google Scholar
• Pons, F., Williams, T. J., Kirk, S. A., McDonald, F. & Rossi, A. G. Pro-inflammatory and anti-inflammatory effects of the stable prostaglandin D2 analogue, ZK 118.182. Eur. J. Pharmacol. 261, 237–247 (1994).
  Article CAS PubMed Google Scholar
• Rajakariar, R. et al. Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyδ12–14 PGJ2 . Proc. Natl Acad. Sci. USA 104, 20979–20984 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Haworth, O. & Buckley, C. D. Resolving the problem of persistence in the switch from acute to chronic inflammation. Proc. Natl Acad. Sci. USA 104, 20647–20648 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Godson, C. et al. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J. Immunol. 164, 1663–1667 (2000). The first demonstration that lipoxins stimulate the uptake of apoptotic neutrophils.
  Article CAS PubMed Google Scholar
• Gronert, K., Gewirtz, A., Madara, J. L. & Serhan, C. N. Identification of a human enterocyte lipoxin A4 receptor that is regulated by IL-13 and IFN-γ and inhibits TNF-α-induced IL-8 release. J. Exp. Med. 187, 1285–1294 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Wallace, J. L. & Fiorucci, S. A magic bullet for mucosal protection. And aspirin is the trigger! Trends Pharmacol. Sci. 24, 323–326 (2003). An authoritative review on the importance of the triggering of endogenous aspirin-triggered lipoxins in gastric mucosal protection.
  Article CAS PubMed Google Scholar
• Colgan, S. P., Serhan, C. N., Parkos, C. A., Delp-Archer, C. & Madara, J. L. Lipoxin A4 modulates transmigration of human neutrophils across intestinal epithelial monolayers. J. Clin. Invest. 92, 75–82 (1993).
  Article CAS PubMed PubMed Central Google Scholar
• Fiore, S. & Serhan, C. N. Formation of lipoxins and leukotrienes during receptor-mediated interactions of human platelets and recombinant human granulocyte/macrophage colony-stimulating factor-primed neutrophils. J. Exp. Med. 172, 1451–1457 (1990).
  Article CAS PubMed Google Scholar
• Romano, M. & Serhan, C. N. Lipoxin generation by permeabilized human platelets. Biochemistry 31, 8269–8277 (1992).
  Article CAS PubMed Google Scholar
• Edenius, C., Haeggstrom, J. & Lindgren, J. A. Transcellular conversion of endogenous arachidonic acid to lipoxins in mixed human platelet-granulocyte suspensions. Biochem. Biophys. Res. Commun. 157, 801–807 (1988).
  Article CAS PubMed Google Scholar
• Freire-de-Lima, C. G. et al. Apoptotic cells, through transforming growth factor-β, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J. Biol. Chem. 281, 38376–38384 (2006).
  Article CAS PubMed Google Scholar
• Vance, R. E., Hong, S., Gronert, K., Serhan, C. N. & Mekalanos, J. J. The opportunistic pathogen Pseudomonas aeruginosa carries a novel secretable arachidonate 15-lipoxygenase. Proc. Natl Acad. Sci. USA 101, 2135–2139 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Aliberti, J., Hieny, S., Reis e Sousa, C., Serhan, C. N. & Sher, A. Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nature Immunol. 3, 76–82 (2002).
  Article CAS Google Scholar
• Bannenberg, G. L., Aliberti, J., Hong, S., Sher, A. & Serhan, C. N. Exogenous pathogen and plant 15-lipoxygenase initiate endogenous lipoxin A4 biosynthesis. J. Exp. Med. 199, 515–523 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Takano, T., Clish, C. B., Gronert, K., Petasis, N. & Serhan, C. N. Neutrophil-mediated changes in vascular permeability are inhibited by topical application of aspirin-triggered 15-epi-lipoxin A4 and novel lipoxin B4 stable analogues. J. Clin. Invest. 101, 819–826 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Chiang, N. et al. The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacol. Rev. 58, 463–487 (2006).
  Article CAS PubMed Google Scholar
• Maddox, J. F. et al. Lipoxin A4 stable analogs are potent mimetics that stimulate human monocytes and THP-1 cells via a G-protein linked lipoxin A4 receptor. J. Biol. Chem. 272, 6972–6978 (1997).
  Article CAS PubMed Google Scholar
• Gronert, K., Colgan, S. P. & Serhan, C. N. Characterization of human neutrophil and endothelial cell ligand-operated extracellular acidification rate by microphysiometry: impact of reoxygenation. J. Pharmacol. Exp. Ther. 285, 252–261 (1998).
  CAS PubMed Google Scholar
• Patcha, V. et al. Differential inside-out activation of β2-integrins by leukotriene B4 and fMLP in human neutrophils. Exp. Cell Res. 300, 308–319 (2004).
  Article CAS PubMed Google Scholar
• Svensson, C. I., Zattoni, M. & Serhan, C. N. Lipoxins and aspirin-triggered lipoxin stop inflammatory pain processing. J. Exp. Med. 204, 245–252 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Vane, J. R. in Les Prix Nobel: Nobel Prizes, Presentations, Biographies and Lectures. 181–206 (Almqvist & Wiksell, Stockholm, 1982).
  Google Scholar
• Clària, J. & Serhan, C. N. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc. Natl Acad. Sci. USA 92, 9475–9479 (1995).
  Article PubMed PubMed Central Google Scholar
• Chiang, N., Bermudez, E. A., Ridker, P. M., Hurwitz, S. & Serhan, C. N. Aspirin triggers anti-inflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc. Natl Acad. Sci. USA 101, 15178–15183 (2004). The first demonstration of the in vivo formation of aspirin-triggered lipid mediators in humans in a double-blind randomized clinical trial.
  Article CAS PubMed PubMed Central Google Scholar
• Nascimento-Silva, V., Arruda, M. A., Barja-Fidalgo, C., Villela, C. G. & Fierro, I. M. Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells. Am. J. Physiol. Cell Physiol. 289, C557–C563 (2005). The first demonstration that lipoxin A 4 stimulates the induction of the HO1 system.
  Article CAS PubMed Google Scholar
• Biteman, B. et al. Interdependence of lipoxin A4 and heme-oxygenase in counter-regulating inflammation during corneal wound healing. FASEB J. 21, 2257–2266 (2007).
  Article CAS PubMed Google Scholar
• Paul-Clark, M. J., van Cao, T., Moradi-Bidhendi, N., Cooper, D. & Gilroy, D. W. 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation. J. Exp. Med. 200, 69–78 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Serhan, C. N. et al. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J. Immunol. 176, 1848–1859 (2006).
  Article CAS PubMed Google Scholar
• Birnbaum, Y. et al. Augmentation of myocardial production of 15-epi-lipoxin-A4 by pioglitazone and atorvastatin in the rat. Circulation 114, 929–935 (2006). This paper reports the discovery that statins stimulate endogenous 15-epi-lipoxin A 4 formation, a potential endogenous anti-inflammatory messenger of the actions of statins.
  Article CAS PubMed Google Scholar
• Ariel, A., Chiang, N., Arita, M., Petasis, N. A. & Serhan, C. N. Aspirin-triggered lipoxin A4 and B4 analogs block extracellular signal-regulated kinase-dependent TNF-α secretion from human T cells. J. Immunol. 170, 6266–6272 (2003).
  Article CAS PubMed Google Scholar
• Kowal-Bielecka, O., Kowal, K., Distler, O. & Gay, S. Mechanisms of disease: leukotrienes and lipoxins in scleroderma lung disease—insights and potential therapeutic implications. Nature Clin. Pract. Rheumatol. 3, 43–51 (2007).
  Article CAS Google Scholar
• Simopoulos, A. P. Omega-3 fatty acids in inflammation and autoimmune diseases. J. Am. Coll. Nutr. 21, 495–505 (2002).
  Article CAS PubMed Google Scholar
• GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 354, 447–455 (1999).
• Lu, Y., Hong, S., Tjonahen, E. & Serhan, C. N. Mediator-lipidomics: databases and search algorithms for PUFA-derived mediators. J. Lipid Res. 46, 790–802 (2005).
  Article CAS PubMed Google Scholar
• Arita, M. et al. Stereochemical assignment, anti-inflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201, 713–722 (2005). This reference provides the complete stereochemical assignment of natural resolvin E1 and its total organic synthesis and interactions with GPCRs.
  Article CAS PubMed PubMed Central Google Scholar
• Winyard, P. G. & Willoughby, D. A. Inflammation Protocols (Humana, Totowa, New Jersey, 2003).
  Book Google Scholar
• Tjonahen, E. et al. Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis. Chem. Biol. 13, 1193–1202 (2006).
  Article CAS PubMed Google Scholar
• Hasturk, H. et al. RvE1 protects from local inflammation and osteoclast mediated bone destruction in periodontitis. FASEB J. 20, 401–403 (2006).
  Article CAS PubMed Google Scholar
• Arita, M. et al. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc. Natl Acad. Sci. USA 102, 7671–7676 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Arita, M. et al. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J. Immunol. 178, 3912–3917 (2007).
  Article CAS PubMed Google Scholar
• Bazan, N. G., Birkle, D. L. & Reddy, T. S. Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina. Biochem. Biophys. Res. Commun. 125, 741–747 (1984).
  Article CAS PubMed Google Scholar
• Salem, N. Jr, Litman, B., Kim, H.-Y. & Gawrisch, K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36, 945–959 (2001). An authoritative review of the important role of the essential fatty acid DHA in neural systems.
  Article CAS PubMed Google Scholar
• Marcheselli, V. L. et al. Novel docosanoids inhibit brain ischemia–reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 278, 43807–43817 (2003). This reference describes the identification of neuroprotectin D1 in vivo in brain ischaemia and its protective role in neural damage.
  Article CAS PubMed Google Scholar
• Sun, Y.-P. et al. Resolvin D1 and its aspirin-triggered 17_R_ epimer: stereochemical assignments, anti-inflammatory properties and enzymatic inactivation. J. Biol. Chem. 282, 9323–9334 (2007).
  Article CAS PubMed Google Scholar
• Wood, P. L. Neuroinflammation: Mechanisms and Management (Humana, Totowa, New Jersey, 1998).
  Book Google Scholar
• Lukiw, W. J. et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115, 2774–2783 (2005). This report provides a demonstration of the role of neuroprotectin D1 in cell survival and its potential deficiency in Alzheimer's disease.
  Article CAS PubMed PubMed Central Google Scholar
• Mukherjee, P. K., Marcheselli, V. L., Serhan, C. N. & Bazan, N. G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc. Natl Acad. Sci. USA 101, 8491–8496 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Ariel, A. et al. The docosatriene protectin D1 is produced by TH2 skewing and promotes human T cell apoptosis via lipid raft clustering. J. Biol. Chem. 280, 43079–43086 (2005).
  Article CAS PubMed Google Scholar
• Mitchell, S. et al. Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo. J. Am. Soc. Nephrol. 13, 2497–2507 (2002). This reference gives an in vivo demonstration of the uptake of apoptotic neutrophils by lipoxins.
  Article CAS PubMed Google Scholar
• Ariel, A. et al. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution via modulation of CCR5 expression. Nature Immunol. 7, 1209–1216 (2006).
  Article CAS Google Scholar
• Serhan, C. N. et al. Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J. Immunol. 171, 6856–6865 (2003).
  Article CAS PubMed Google Scholar
• Shen, J. et al. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. J. Clin. Invest. 98, 2201–2208 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Mangino, M. J., Brounts, L., Harms, B. & Heise, C. Lipoxin biosynthesis in inflammatory bowel disease. Prostaglandins Other Lipid Mediat. 79, 84–92 (2006).
  Article CAS PubMed Google Scholar
• Fiorucci, S. et al. A β-oxidation-resistant lipoxin A4 analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction. Proc. Natl Acad. Sci. USA 101, 15736–15741 (2004). The first demonstration that the second-generation lipoxin stable analogues are protective in models of gastrointestinal inflammation.
  Article CAS PubMed PubMed Central Google Scholar
• Gronert, K. et al. A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense. J. Biol. Chem. 280, 15267–15278 (2005).
  Article CAS PubMed Google Scholar
• Basile, D. P., Donohoe, D., Roethe, K. & Osborn, J. L. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am. J. Physiol. Renal Physiol. 281, F887–F899 (2001).
  Article CAS PubMed Google Scholar
• Duffield, J. S. et al. Resolvin D series and protectin D1 mitigate acute kidney injury. J. Immunol. 177, 5902–5911 (2006).
  Article CAS PubMed Google Scholar
• González-Périz, A. et al. Docosahexanenoic acid (DHA) blunts liver injury by conversion to protective lipid mediators: protectin D1 and 17_S_-hydroxy-DHA. FASEB J. 20, 2537–2539 (2006).
  Article PubMed CAS Google Scholar
• Levy, B. D. et al. Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A4 . Nature Med. 8, 1018–1023 (2002).
  Article CAS PubMed Google Scholar
• Levy, B. D. et al. Diminished lipoxin biosynthesis in severe asthma. Am. J. Respir. Crit. Care Med. 172, 824–830 (2005).
  Article PubMed PubMed Central Google Scholar
• Levy, B. D. et al. Protectin D1 is generated in asthma and dampens airway inflammation and hyper-responsiveness. J. Immunol. 178, 496–502 (2007).
  Article CAS PubMed Google Scholar
• Gilroy, D. W. et al. Inducible cycloxygenase may have anti-inflammatory properties. Nature Med. 5, 698–701 (1999).
  Article CAS PubMed Google Scholar
• Rossi, A. G. & Sawatzky, D. A. The Resolution of Inflammation (Birkhäuser Verlag AG, Basel, 2007).
  Google Scholar
• Serhan, C. N. et al. Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils. Biochemistry 34, 14609–14615 (1995).
  Article CAS PubMed Google Scholar
• Rossi, A. G. et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nature Med. 12, 1056–1064 (2006).
  Article CAS PubMed Google Scholar
• Karp, C. L. et al. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nature Immunol. 5, 388–392 (2004). This reference demonstrates that lipoxins are anti-inflammatory and protective in a model of cystic fibrosis.
  Article CAS Google Scholar
• Hudert, C. A. et al. Transgenic mice rich in endogenous n-3 fatty acids are protected from colitis. Proc. Natl Acad. Sci. USA 103, 11276–11281 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Xia, S. et al. Melanoma growth is reduced in fat-1 transgenic mice: impact of omega-6/omega-3 essential fatty acids. Proc. Natl Acad. Sci. USA 103, 12499–12504 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Jozsef, L., Zouki, C., Petasis, N. A., Serhan, C. N. & Filep, J. G. Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-κB and AP-1 activation, and IL-8 gene expression in human leukocytes. Proc. Natl Acad. Sci. USA 99, 13266–13271 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Filep, J. G., Zouki, C., Petasis, N. A., Hachicha, M. & Serhan, C. N. Anti-inflammatory actions of lipoxin A4 stable analogs are demonstrable in human whole blood: modulation of leukocyte adhesion molecules and inhibition of neutrophil-endothelial interactions. Blood 94, 4132–4142 (1999).
  CAS PubMed Google Scholar
• Papayianni, A., Serhan, C. N. & Brady, H. R. Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells. J. Immunol. 156, 2264–2272 (1996).
  CAS PubMed Google Scholar
• Levy, B. D. et al. Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a “stop” signaling switch for aspirin-triggered lipoxin A4 . FASEB J. 13, 903–911 (1999).
  Article CAS PubMed Google Scholar
• Fiore, S. & Serhan, C. N. Lipoxin A4 receptor activation is distinct from that of the formyl peptide receptor in myeloid cells: inhibition of CD11/18 expression by lipoxin A4-lipoxin A4 receptor interaction. Biochemistry 34, 16678–16686 (1995).
  Article CAS PubMed Google Scholar
• Bandeira-Melo, C. et al. Cutting edge: lipoxin (LX) A4 and aspirin-triggered 15-epi-LXA4 block allergen-induced eosinophil trafficking. J. Immunol. 164, 2267–2271 (2000).
  Article CAS PubMed Google Scholar
• Lee, T. H. et al. Lipoxin A4 and lipoxin B4 inhibit chemotactic responses of human neutrophils stimulated by leukotriene B4 and N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Clin. Sci. 77, 195–203 (1989).
  Article CAS Google Scholar
• Bonnans, C. et al. Lipoxins are potential endogenous antiinflammatory mediators in asthma. Am. J. Respir. Crit. Care Med. 165, 1531–1535 (2002).
  Article PubMed Google Scholar
• Gewirtz, A. T. et al. 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 (2002).
  Article CAS PubMed Google Scholar
• Gewirtz, A. T. et al. Pathogen-induced chemokine secretion from model intestinal epithelium is inhibited by lipoxin A4 analogs. J. Clin. Invest. 101, 1860–1869 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Brezinski, M. E., Gimbrone, M. A. Jr, Nicolaou, K. C. & Serhan, C. N. Lipoxins stimulate prostacyclin generation by human endothelial cells. FEBS Lett. 245, 167–172 (1989).
  Article CAS PubMed Google Scholar
• Nascimento-Silva, V., Arruda, M. A., Barja-Fidalgo, C. & Fierro, I. M. Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: a novel antioxidative mechanism. Thromb. Haemost. 97, 88–98 (2007).
  Article CAS PubMed Google Scholar
• Cezar-de-Mello, P. F., Nascimento-Silva, V., Villela, C. G. & Fierro, I. M. Aspirin-triggered lipoxin A4 inhibition of VEGF-induced endothelial cell migration involves actin polymerization and focal adhesion assembly. Oncogene 25, 122–129 (2006).
  Article CAS PubMed Google Scholar
• Sodin-Semrl, S., Taddeo, B., Tseng, D., Varga, J. & Fiore, S. Lipoxin A4 inhibits IL-1β-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases. J. Immunol. 164, 2660–2666 (2000).
  Article CAS PubMed Google Scholar
• Wu, S. H., Wu, X. H., Lu, C., Dong, L. & Chen, Z. Q. Lipoxin A4 inhibits proliferation of human lung fibroblasts induced by connective tissue growth factor. Am. J. Respir. Cell Mol. Biol. 34, 65–72 (2006).
  Article CAS PubMed Google Scholar
• Planagumà, A. et al. Aspirin (ASA) regulates 5-lipoxygenase activity and peroxisome proliferator-activated receptor a-mediated CINC-1 release in rat liver cells: novel actions of lipoxin A4 (LXA4) and ASA-triggered 15-epi-LXA4 . FASEB J. 16, 1937–1939 (2002).
  Article PubMed CAS Google Scholar
• McMahon, B. et al. Lipoxin A4 antagonizes the mitogenic effects of leukotriene D4 in human renal mesangial cells: differential activation of MAP kinases through distinct receptors. J. Biol. Chem. 275, 27566–27575 (2000).
  CAS PubMed Google Scholar
• Wu, S. H. et al. Lipoxin A4 inhibits connective tissue growth factor-induced production of chemokines in rat mesangial cells. Kidney Int. 69, 248–256 (2006).
  Article CAS PubMed Google Scholar
• Wada, K. et al. Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation. FASEB J. 20, 1785–1792 (2006).
  Article CAS PubMed Google Scholar
• Clish, C. B. et al. Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo. Proc. Natl Acad. Sci. USA 96, 8247–8252 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Takano, T. et al. Aspirin-triggered 15-epi-lipoxin A4 and LXA4 stable analogs are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. J. Exp. Med. 185, 1693–1704 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Chiang, N. et al. Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion. J. Clin. Invest. 104, 309–316 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Scalia, R., Gefen, J., Petasis, N. A., Serhan, C. N. & Lefer, A. M. Lipoxin A4 stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: role of P-selectin. Proc. Natl Acad. Sci. USA 94, 9967–9972 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Fierro, I. M., Kutok, J. L. & Serhan, C. N. Novel lipid mediator regulators of endothelial cell proliferation and migration: aspirin-triggered-15_R_-lipoxin A4 and lipoxin A4 . J. Pharmacol. Exp. Ther. 300, 385–392 (2002).
  Article CAS PubMed Google Scholar
• Devchand, P. R. et al. A synthetic eicosanoid LX-mimetic unravels host-donor interactions in allogeneic BMT-induced GvHD to reveal an early protective role for host neutrophils. FASEB J. 19, 203–210 (2005).
  Article CAS PubMed Google Scholar
• Munger, K. A. et al. Transfection of rat kidney with human 15-lipoxygenase suppresses inflammation and preserves function in experimental glomerulonephritis. Proc. Natl Acad. Sci. USA 96, 13375–13380 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Connor, K. M. et al. Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nature Med. 13, 868–873 (2007).
  Article CAS PubMed Google Scholar