Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?
Because inflammation is appreciated as a unifying basis of many widely occurring diseases, the mechanisms involved in its natural resolution are of considerable interest. Using contained, self-limited inflammatory exudates and a systems approach, novel lipid-derived mediators and pathways were uncovered in the resolution of inflammatory exudates. These new families of local mediators control both the duration and magnitude of acute inflammation as well as the return of the site to homeostasis in the process of catabasis. This new genus of specialized proresolving mediators (SPM) includes essential fatty acid-derived lipoxins, resolvins, protectins, and, most recently, maresins. These families were named based on their unique structures and potent stereoselective actions. The temporally initiated biosynthesis of SPM and their direct impact on leukocyte trafficking and macrophage-directed clearance mechanisms provide clear evidence that resolution is an active, programmed response at the tissue level. Moreover, SPM that possess anti-inflammatory (ie, limiting PMN infiltration) and proresolving (enhance macrophage uptake and clearance of apoptotic PMN and microbial particles) actions as well as stimulating mucosal antimicrobial responses demonstrate that anti-inflammation and proresolution are different responses of the host and novel defining properties of these molecules. The mapping of new resolution circuits has opened the possibility for understanding mechanisms that lead from acute to chronic inflammation, or to the resolution thereof, as well as to potential, resolution-based immunopharmacological therapies.
Serhan
Charles N
CN
Director, Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 8, Boston, MA 02115, USA. cnserhan@zeus.bwh.harvard.edu
D000818:Animals; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D018836:Inflammation Mediators / Q000502:physiology*; D008055:Lipids / Q000502:physiology*; D015398:Signal Transduction
D018836:Inflammation Mediators; D008055:Lipids
Prog Lipid Res. 2008 Mar;47(2):77-106
18177743
Biochem J. 2005 May 1;387(Pt 3):695-702
15588254
Nat Rev Drug Discov. 2004 May;3(5):401-16
15136788
J Exp Med. 2005 Mar 7;201(5):713-22
15753205
J Exp Med. 2008 Nov 24;205(12):2791-801
18955568
FASEB J. 2007 Feb;21(2):325-32
17267386
Prostaglandins Other Lipid Mediat. 2006 Sep;80(3-4):123-35
16939877
Nat Immunol. 2002 Nov;3(11):1041-7
12407413
Curr Opin Pharmacol. 2005 Aug;5(4):405-11
15955733
Nat Med. 2002 Sep;8(9):1018-23
12172542
J Immunol. 2007 Jan 1;178(1):496-502
17182589
J Immunol. 2008 Mar 1;180(5):3512-9
18292578
Org Lett. 2009 Aug 20;11(16):3602-5
19637859
Scand J Immunol. 2004 Sep;60(3):249-56
15320881
Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11276-81
16847262
J Biol Chem. 2006 Aug 11;281(32):22847-54
16757471
PLoS One. 2008 Apr 02;3(4):e1879
18382663
Annu Rev Immunol. 2007;25:101-37
17090225
FASEB J. 2009 Jun;23(6):1946-57
19211925
Lipids. 2001 Sep;36(9):945-59
11724467
J Exp Med. 1994 Jul 1;180(1):253-60
8006586
Diabetologia. 2006 Sep;49(9):2109-19
16783472
Science. 2001 Nov 30;294(5548):1871-5
11729303
J Clin Invest. 2005 Oct;115(10):2774-83
16151530
Blood. 2009 May 28;113(22):5650-9
19346498
Circ Res. 2009 Nov 20;105(11):1072-82
19834009
J Immunol. 2003 Dec 15;171(12):6856-65
14662892
Br J Pharmacol. 2008 Mar;153 Suppl 1:S200-15
17965751
FASEB J. 2008 Oct;22(10):3595-606
18559988
Anesthesiology. 1995 Apr;82(4):1026-60
7717537
Br J Pharmacol. 2006 Jan;147 Suppl 1:S182-92
16402103
Trends Pharmacol Sci. 2003 Jul;24(7):323-6
12871661
Annu Rev Pathol. 2006;1:215-42
18039114
Science. 1987 Sep 4;237(4819):1171-6
2820055
Nat Rev Cancer. 2006 Feb;6(2):130-40
16491072
J Immunol. 2006 Feb 1;176(3):1848-59
16424216
Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3613-20
19443724
Biochem J. 1960 Mar;74:427-9
14430870
Nat Med. 1999 Jun;5(6):698-701
10371510
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1660-5
20080636
Am J Respir Crit Care Med. 2005 May 15;171(10):1070-6
15695494
Chest. 1991 Mar;99(3 Suppl):2S-6S
1997264
J Thromb Haemost. 2009 Jul;7 Suppl 1:332-9
19630828
Prostaglandins Leukot Essent Fatty Acids. 2010 Apr-Jun;82(4-6):319-25
20202804
Annu Rev Pathol. 2008;3:99-126
18039143
J Exp Med. 2008 Apr 14;205(4):767-75
18391062
Allergy. 2009 Dec;64(12):1746-52
19385948
Nature. 2009 Oct 29;461(7268):1287-91
19865173
J Am Coll Nutr. 2002 Dec;21(6):495-505
12480795
J Exp Med. 1997 May 5;185(9):1693-704
9151906
J Exp Med. 2000 Oct 16;192(8):1197-204
11034610
FASEB J. 2009 Mar;23(3):844-54
18971259
FASEB J. 2006 Feb;20(2):401-3
16373400
J Immunol. 2008 Sep 1;181(5):3515-23
18714024
Nat Immunol. 2006 Nov;7(11):1209-16
17013391
J Exp Med. 2009 Jan 16;206(1):15-23
19103881
J Exp Med. 2007 Feb 19;204(2):245-52
17242163
FASEB J. 2004 Mar;18(3):489-98
15003994
PLoS One. 2007 Dec 19;2(12):e1316
18091990
J Exp Med. 1996 Jan 1;183(1):137-46
8551217
Nat Immunol. 2009 Mar;10(3):281-8
19198593
J Endocrinol. 2003 Jul;178(1):29-36
12844333
J Immunol. 2008 Dec 15;181(12):8677-87
19050288
Nat Immunol. 2005 Dec;6(12):1191-7
16369558
Br J Pharmacol. 2009 Oct;158(4):1059-61
19845687
Nat Rev Immunol. 2010 Jan;10(1):36-46
19960040
J Biol Chem. 2006 Dec 15;281(50):38376-84
17056601
Curr Opin Drug Discov Devel. 2009 Sep;12(5):644-58
19736623
Monogr Pathol. 1982;(23):1-17
6750363
J Immunol. 2009 Sep 1;183(5):3383-9
19675173
J Biol Chem. 2005 Apr 15;280(15):15267-78
15708862
Proc Natl Acad Sci U S A. 2005 May 24;102(21):7671-6
15890784
J Immunol. 2009 May 1;182(9):5374-81
19380784
J Nutr. 2009 Jan;139(1):5-10
19056654
Prostaglandins Leukot Essent Fatty Acids. 2010 Jan;82(1):27-34
19931440
Pharmacol Rev. 2009 Jun;61(2):119-61
19498085
BMJ. 2008 Dec 23;337:a2931
19106137
Annu Rev Pharmacol Toxicol. 2009;49:123-50
18834304
Cell. 2010 Mar 5;140(5):615-8
20211131
Trends Immunol. 2006 Jan;27(1):24-31
16316783
Lancet. 1999 Aug 7;354(9177):447-55
10465168
Histochem Cell Biol. 2004 Oct;122(4):305-21
15322859
Nat Struct Mol Biol. 2008 Sep;15(9):924-31
19172745
Science. 1983 May 6;220(4597):568-75
6301011
Biochem Biophys Res Commun. 2008 Mar 7;367(2):509-15
18190790
Haematologica. 2009 Feb;94(2):258-63
19109217
J Immunol. 2005 Apr 1;174(7):4345-55
15778399
Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15178-83
15471991
Am J Clin Nutr. 2006 Jun;83(6 Suppl):1467S-1476S
16841856
J Immunol. 2009 Mar 1;182(5):3223-32
19234220
Mol Vis. 2010 Mar 02;16:320-9
20216940
J Biol Chem. 2007 Mar 30;282(13):9323-9334
17244615
Blood. 2008 Aug 1;112(3):848-55
18480426
J Exp Med. 2002 Oct 21;196(8):1025-37
12391014
Nat Med. 2006 Sep;12(9):1056-64
16951685
Biochimie. 2009 Jun;91(6):791-5
19455748
Prostaglandins Leukot Essent Fatty Acids. 2005 Sep-Oct;73(3-4):141-62
16005201
Inflamm Bowel Dis. 2010 Jan;16(1):87-95
19572372
Circulation. 2006 Aug 29;114(9):929-35
16908763
Prostaglandins Leukot Essent Fatty Acids. 2009 Apr;80(4):177-83
19264468
Am J Physiol Renal Physiol. 2004 Feb;286(2):F189-201
14707005
Am J Pathol. 2009 Jan;174(1):115-22
19095947
Nat Immunol. 2004 Apr;5(4):388-92
15034576
Nat Immunol. 2008 Aug;9(8):873-9
18568027
J Immunol. 2009 Aug 1;183(3):2089-96
19597002
Chem Biol. 2006 Nov;13(11):1193-202
17114001
Nat Immunol. 2001 Jul;2(7):612-9
11429545
J Biol Chem. 2003 Apr 25;278(17):14677-87
12590139
J Biol Chem. 2009 May 29;284(22):14744-59
19324874
J Immunol. 2000 Feb 15;164(4):1663-7
10657608
Genomics. 1998 Jun 1;50(2):281-6
9653656
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2135-9
14766977
J Clin Invest. 1998 Feb 15;101(4):819-26
9466977
Int J Exp Pathol. 2007 Apr;88(2):85-94
17408451
Nat Rev Immunol. 2008 May;8(5):349-61
18437155
J Immunol. 2006 Nov 1;177(9):5902-11
17056514
FASEB J. 2007 Oct;21(12):3162-70
17496159
J Immunol. 2007 Mar 15;178(6):3912-7
17339491
J Exp Med. 2004 Feb 16;199(4):515-23
14970178
J Immunol. 2010 Feb 1;184(3):1516-25
20032295
Cell. 2010 Mar 5;140(5):717-30
20211140
J Biol Chem. 2010 Jan 29;285(5):3451-61
19906641
Biochem Biophys Res Commun. 2005 Dec 9;338(1):149-57
16112645
J Clin Invest. 2005 Jun;115(6):1601-6
15931391
Arterioscler Thromb Vasc Biol. 2006 Feb;26(2):e14-7
16293793
J Biol Chem. 2003 Oct 31;278(44):43807-17
12923200
Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9475-9
7568157
Biochem Biophys Res Commun. 1984 Dec 14;125(2):741-7
6240268
J Biol Chem. 2009 Aug 7;284(32):21599-612
19487688
J Immunol. 2010 Mar 1;184(5):2611-2619
20107188
J Immunol. 2010 Jan 15;184(2):836-43
20007539
Nat Immunol. 2000 Jul;1(1):83-7
10881180
Pharmacol Rev. 2006 Sep;58(3):463-87
16968948
Nat Med. 2007 Jul;13(7):868-873
17589522
FASEB J. 2003 Apr;17(6):652-9
12665478
Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8491-6
15152078
Blood. 2008 Nov 15;112(10):4117-27
18779392
Invest Ophthalmol Vis Sci. 2009 Oct;50(10):4743-52
19407006
J Immunol. 2008 Oct 1;181(7):4534-44
18802056
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3902-7
11891303
Semin Hematol. 1997 Oct;34(4):279-90
9347578
Nat Rev Immunol. 2003 Sep;3(9):710-20
12949495
J Biol Chem. 2005 Dec 30;280(52):43079-86
16216871
Nature. 2007 Jun 14;447(7146):869-74
17568749
AAPS J. 2006 Apr 28;8(2):E284-97
16796379