title: The therapeutic potential of carbon monoxide.
abstract: Carbon monoxide (CO) is increasingly being accepted as a cytoprotective and homeostatic molecule with important signalling capabilities in physiological and pathophysiological situations. The endogenous production of CO occurs through the activity of constitutive (haem oxygenase 2) and inducible (haem oxygenase 1) haem oxygenases, enzymes that are responsible for the catabolism of haem. Through the generation of its products, which in addition to CO includes the bile pigments biliverdin, bilirubin and ferrous iron, the haem oxygenase 1 system also has an obligatory role in the regulation of the stress response and in cell adaptation to injury. This Review provides an overview of the physiology of CO, summarizes the effects of CO gas and CO-releasing molecules in preclinical animal models of cardiovascular disease, inflammatory disorders and organ transplantation, and discusses the development and therapeutic options for the exploitation of this simple gaseous molecule.
authors.affiliation: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, Genoa, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D016377:Organ Transplantation / Q000379:methods; D015398:Signal Transduction
chemical_list: D002248:Carbon Monoxide
references.citation: Arthritis Rheum. 2008 Nov;58(11):3388-93
references.pmid: 18975324
references.citation: J Immunol. 1992 Aug 15;149(4):1416-23
references.pmid: 1386865
references.citation: Mol Pharmacol. 1987 Oct;32(4):497-504
references.pmid: 2890093
references.citation: Experientia. 1990 Dec 1;46(11-12):1202-6
references.pmid: 2174793
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G236-44
references.pmid: 18006605
references.citation: Circ Res. 2007 Oct 26;101(9):862-4
references.pmid: 17967796
references.citation: Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2772-8
references.pmid: 16844915
references.citation: J Nucl Med. 1983 May;24(5):431-7
references.pmid: 6405020
references.citation: FASEB J. 2004 Apr;18(6):771-2
references.pmid: 14977880
references.citation: Arterioscler Thromb Vasc Biol. 2010 Jan;30(1):98-104
references.pmid: 19875720
references.citation: J Immunol. 2001 Mar 15;166(6):4185-94
references.pmid: 11238670
references.citation: J Pharmacol Exp Ther. 2006 Sep;318(3):1315-22
references.pmid: 16772536
references.citation: Nat Med. 2003 Feb;9(2):183-90
references.pmid: 12539038
references.citation: Hypertens Res. 2007 Apr;30(4):341-8
references.pmid: 17541213
references.citation: Blood Vessels. 1991;28(1-3):52-61
references.pmid: 1848126
references.citation: FASEB J. 2004 May;18(7):854-6
references.pmid: 15001560
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G184-91
references.pmid: 17991708
references.citation: J Cell Sci. 2007 Jan 15;120(Pt 2):299-308
references.pmid: 17179207
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925-30
references.pmid: 9380736
references.citation: Liver Transpl. 2009 Nov;15(11):1458-68
references.pmid: 19877256
references.citation: Am J Physiol. 1999 Apr;276(4):L688-94
references.pmid: 10198367
references.citation: Hypertension. 2007 Dec;50(6):1040-8
references.pmid: 17923586
references.citation: J Clin Invest. 2008 Jan;118(1):239-47
references.pmid: 18060048
references.citation: J Pharmacol Exp Ther. 2007 May;321(2):656-62
references.pmid: 17289832
references.citation: Chest. 1999 Oct;116(4):1007-11
references.pmid: 10531166
references.citation: J Physiol. 1912 Jun 12;44(4):275-304
references.pmid: 16993128
references.citation: J Pharmacol Toxicol Methods. 2006 Nov-Dec;54(3):288-95
references.pmid: 16540352
references.citation: J Biol Chem. 2005 Mar 11;280(10):8714-21
references.pmid: 15590660
references.citation: Hepatology. 2002 Apr;35(4):815-23
references.pmid: 11915027
references.citation: Gastroenterology. 2003 Feb;124(2):377-91
references.pmid: 12557144
references.citation: Nat Rev Drug Discov. 2007 Nov;6(11):917-35
references.pmid: 17948022
references.citation: Hypertension. 2009 Mar;53(3):508-15
references.pmid: 19171794
references.citation: Am J Pathol. 2009 Jul;175(1):422-9
references.pmid: 19498004
references.citation: Shock. 2005 Jun;23(6):527-32
references.pmid: 15897805
references.citation: Life Sci. 2007 Apr 3;80(17):1619-26
references.pmid: 17321552
references.citation: Am J Physiol Gastrointest Liver Physiol. 2005 Sep;289(3):G607-13
references.pmid: 15890710
references.citation: Am J Physiol Heart Circ Physiol. 2004 May;286(5):H1649-53
references.pmid: 14704226
references.citation: J Clin Invest. 2007 Dec;117(12):3730-41
references.pmid: 18037988
references.citation: Diabetes. 2007 May;56(5):1240-7
references.pmid: 17303808
references.citation: Br J Pharmacol. 2005 Jul;145(6):800-10
references.pmid: 15880142
references.citation: Nat Med. 2000 Apr;6(4):422-8
references.pmid: 10742149
references.citation: J Biol Chem. 1997 Mar 28;272(13):8222-6
references.pmid: 9079640
references.citation: FASEB J. 2005 Feb;19(2):284-6
references.pmid: 15556971
references.citation: Curr Pharm Des. 2003;9(30):2525-39
references.pmid: 14529551
references.citation: FASEB J. 2004 Jul;18(10):1093-5
references.pmid: 15132974
references.citation: World J Gastroenterol. 2007 Dec 14;13(46):6183-90
references.pmid: 18069757
references.citation: FASEB J. 2005 Mar;19(3):458-60
references.pmid: 15640283
references.citation: Cardiovasc Res. 2006 Jul 15;71(2):393-401
references.pmid: 16713591
references.citation: Nat Med. 2001 May;7(5):598-604
references.pmid: 11329062
references.citation: J Exp Med. 2000 Oct 2;192(7):1015-26
references.pmid: 11015442
references.citation: Circ Res. 2007 Oct 26;101(9):919-27
references.pmid: 17823375
references.citation: J Exp Med. 2005 Jul 18;202(2):283-94
references.pmid: 16027238
references.citation: Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H2009-15
references.pmid: 15217799
references.citation: Am J Physiol Renal Physiol. 2006 Feb;290(2):F324-34
references.pmid: 16131650
references.citation: J Biol Chem. 2003 Jun 13;278(24):22061-70
references.pmid: 12690100
references.citation: J Clin Invest. 2006 Mar;116(3):808-16
references.pmid: 16485041
references.citation: Dalton Trans. 2007 May 7;(17):1651-60
references.pmid: 17443255
references.citation: Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):305-12
references.pmid: 19965783
references.citation: Proc Natl Acad Sci U S A. 1968 Oct;61(2):748-55
references.pmid: 4386763
references.citation: Br J Pharmacol. 2006 Oct;149(4):345-54
references.pmid: 16953189
references.citation: Resuscitation. 2007 Feb;72(2):306-18
references.pmid: 17092627
references.citation: Ren Fail. 2007;29(5):543-8
references.pmid: 17654315
references.citation: J Cell Sci. 2006 Jun 1;119(Pt 11):2291-8
references.pmid: 16723735
references.citation: Annu Rev Pharmacol Toxicol. 1997;37:517-54
references.pmid: 9131263
references.citation: Am J Physiol Renal Physiol. 2004 Nov;287(5):F979-89
references.pmid: 15292046
references.citation: Br J Ophthalmol. 2009 Feb;93(2):254-7
references.pmid: 18977789
references.citation: J Exp Med. 2006 Sep 4;203(9):2109-19
references.pmid: 16908624
references.citation: Science. 2002 Dec 20;298(5602):2385-7
references.pmid: 12446832
references.citation: Antioxid Redox Signal. 2004 Oct;6(5):841-9
references.pmid: 15345144
references.citation: J Surg Res. 2007 Mar;138(1):121-7
references.pmid: 17196991
references.citation: Gut. 2009 Mar;58(3):347-56
references.pmid: 19022916
references.citation: J Pharmacol Exp Ther. 2009 May;329(2):641-8
references.pmid: 19190234
references.citation: Intensive Care Med. 2008 Apr;34(4):649-58
references.pmid: 18286265
references.citation: Transplantation. 2006 Jan 27;81(2):220-30
references.pmid: 16436966
references.citation: Am J Respir Cell Mol Biol. 2009 Aug;41(2):129-35
references.pmid: 19097991
references.citation: Crit Care. 2009;13(4):220
references.pmid: 19691819
references.citation: FASEB J. 2009 Apr;23(4):1023-31
references.pmid: 19095732
references.citation: World J Gastroenterol. 2008 Jan 28;14(4):547-53
references.pmid: 18203286
references.citation: J Exp Med. 2005 Dec 19;202(12):1703-13
references.pmid: 16365149
references.citation: Gut. 2003 Sep;52(9):1278-85
references.pmid: 12912858
references.citation: N Engl J Med. 2007 Mar 8;356(10):998-1008
references.pmid: 17296824
references.citation: Am J Transplant. 2010 Apr;10(4):763-772
references.pmid: 20199500
references.citation: Antioxid Redox Signal. 2007 Dec;9(12):2139-55
references.pmid: 17854278
references.citation: J Mol Cell Cardiol. 1990 Jun;22(6):687-95
references.pmid: 2231736
references.citation: Am J Physiol Renal Physiol. 2009 Jul;297(1):F19-26
references.pmid: 19369289
references.citation: J Biol Chem. 2005 Jul 8;280(27):25350-60
references.pmid: 15863496
references.citation: J Clin Invest. 2007 Feb;117(2):438-47
references.pmid: 17256058
references.citation: Pharmacol Rev. 2008 Mar;60(1):79-127
references.pmid: 18323402
references.citation: Expert Opin Ther Pat. 2009 May;19(5):663-82
references.pmid: 19441940
references.citation: Circ Res. 2003 Jul 25;93(2):e2-8
references.pmid: 12842916
references.citation: Kidney Int. 2004 Feb;65(2):564-74
references.pmid: 14717926
references.citation: Hepatology. 2003 Oct;38(4):909-18
references.pmid: 14512878
references.citation: Am J Pathol. 2003 Dec;163(6):2555-63
references.pmid: 14633627
references.citation: J Immunol. 2007 Dec 1;179(11):7840-51
references.pmid: 18025230
references.citation: Arterioscler Thromb Vasc Biol. 2004 Oct;24(10):1848-53
references.pmid: 15308554
references.citation: Am J Respir Cell Mol Biol. 2009 Jul;41(1):85-92
references.pmid: 19097987
references.citation: Circ Res. 2002 Feb 8;90(2):E17-24
references.pmid: 11834719
references.citation: Trends Biochem Sci. 2006 Nov;31(11):614-21
references.pmid: 16996273
references.citation: Mol Pharmacol. 2009 Jul;76(1):173-82
references.pmid: 19366789
references.citation: Am J Physiol Renal Physiol. 2008 Oct;295(4):F1207-12
references.pmid: 18715939
references.citation: Science. 1993 Jun 25;260(5116):1946-50
references.pmid: 8100368
references.citation: Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1243-53
references.pmid: 19617415
references.citation: Shock. 2007 Feb;27(2):165-71
references.pmid: 17224791
references.citation: Am J Physiol Renal Physiol. 2008 Mar;294(3):F508-17
references.pmid: 18094035
references.citation: Kidney Int. 2008 Oct;74(8):1009-16
references.pmid: 18633343
references.citation: Transplantation. 2008 Feb 27;85(4):576-81
references.pmid: 18347537
references.citation: Biochemistry. 2009 Feb 24;48(7):1613-9
references.pmid: 19183042
references.citation: Anesthesiology. 2008 Jun;108(6):1025-36
references.pmid: 18497603
references.citation: Am J Pathol. 2005 Jan;166(1):27-37
references.pmid: 15631997
references.citation: Liver Int. 2009 May;29(5):650-60
references.pmid: 18795901
references.citation: Antioxid Redox Signal. 2007 Dec;9(12):2175-85
references.pmid: 17919067
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Dec;285(6):L1270-6
references.pmid: 12896878
references.citation: Biochem Biophys Res Commun. 2006 Feb 17;340(3):935-43
references.pmid: 16403456
references.citation: J Mol Med (Berl). 2008 Mar;86(3):267-79
references.pmid: 18034222
references.citation: Free Radic Biol Med. 2008 Sep 1;45(5):562-9
references.pmid: 18549826
references.citation: Am J Physiol Heart Circ Physiol. 2009 Sep;297(3):H920-9
references.pmid: 19561312
references.citation: Kidney Int. 2006 Jan;69(2):239-47
references.pmid: 16408112
references.citation: Science. 2002 Dec 20;298(5602):2339-40
references.pmid: 12493901
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jul;295(1):G146-G152
references.pmid: 18497334
references.citation: FASEB J. 2005 Jan;19(1):106-8
references.pmid: 15514102
references.citation: Inflammation. 2009 Dec;32(6):364-71
references.pmid: 19705266
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5191-6
references.pmid: 16551742
references.citation: J Biol Chem. 2004 Oct 22;279(43):44327-34
references.pmid: 15280387
references.citation: FASEB J. 2007 Apr;21(4):1099-106
references.pmid: 17264172
references.citation: Nature. 2003 Oct 2;425(6957):531-5
references.pmid: 14523450
references.citation: Am J Physiol Renal Physiol. 2006 Apr;290(4):F789-94
references.pmid: 16291575
references.citation: J Clin Invest. 1992 Jul;90(1):267-70
references.pmid: 1634613
references.citation: Biochem J. 1927;21(5):1068-75
references.pmid: 16743934
references.citation: Am J Pathol. 2003 Oct;163(4):1587-98
references.pmid: 14507665
references.citation: FASEB J. 2007 Nov;21(13):3450-7
references.pmid: 17551098
references.citation: Cell Cycle. 2007 Jan 1;6(1):39-43
references.pmid: 17245120
references.citation: J Vasc Surg. 2006 Jul;44(1):151-8
references.pmid: 16828440
references.citation: Nat Med. 2007 Jun;13(6):703-10
references.pmid: 17496899
references.citation: Br J Pharmacol. 2004 Jun;142(3):453-60
references.pmid: 15148243
references.citation: Surgery. 2003 Aug;134(2):285-92
references.pmid: 12947331
references.citation: Physiology (Bethesda). 2009 Feb;24:26-35
references.pmid: 19196649
references.citation: Crit Care Med. 2005 Jun;33(6):1317-26
references.pmid: 15942350
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):4039-43
references.pmid: 18316727
references.citation: J Heart Lung Transplant. 2007 Nov;26(11):1192-8
references.pmid: 18022087
references.citation: Cardiovasc Res. 2005 Feb 15;65(3):751-61
references.pmid: 15664403
references.citation: Pharmacol Res. 2006 Jul;54(1):24-9
references.pmid: 16524742
references.citation: Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2501-7
references.pmid: 17630349
references.citation: Eur J Pediatr. 2005 Mar;164(3):162-5
references.pmid: 15599764
references.citation: Antioxid Redox Signal. 2002 Apr;4(2):259-70
references.pmid: 12006177
references.citation: J Cell Mol Med. 2006 Jul-Sep;10(3):650-71
references.pmid: 16989726
references.citation: J Asthma. 2009 Sep;46(7):665-9
references.pmid: 19728202
references.citation: Antioxid Redox Signal. 2002 Aug;4(4):615-24
references.pmid: 12230873
references.citation: Ann Rheum Dis. 2008 Sep;67(9):1211-7
references.pmid: 18063671
references.citation: Cardiovasc Res. 2010 May 1;86(2):338-45
references.pmid: 20167573
references.citation: J Thorac Cardiovasc Surg. 2008 Oct;136(4):1067-75
references.pmid: 18954651
references.citation: Cardiovasc Res. 2007 Jul 15;75(2):339-48
references.pmid: 17544387
references.citation: Am J Hum Genet. 2000 Jan;66(1):187-95
references.pmid: 10631150
references.citation: Am J Transplant. 2006 Oct;6(10):2243-55
references.pmid: 16827783
references.citation: Hepatology. 2003 Apr;37(4):810-23
references.pmid: 12668974
references.citation: Immunity. 2006 May;24(5):601-10
references.pmid: 16713977
references.citation: Am J Epidemiol. 2009 Sep 15;170(6):747-56
references.pmid: 19696228
references.citation: FASEB J. 2008 Sep;22(9):3380-8
references.pmid: 18556460
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5109-14
references.pmid: 17360382
references.citation: Cryobiology. 2009 Jun;58(3):248-55
references.pmid: 19444967
references.citation: Crit Care Med. 2005 Jun;33(6):1445-6
references.pmid: 15942382
references.citation: Physiol Rev. 2006 Apr;86(2):583-650
references.pmid: 16601269
references.citation: Expert Opin Investig Drugs. 2005 Nov;14(11):1305-18
references.pmid: 16255672
references.citation: Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H304-9
references.pmid: 14684363
references.citation: Circulation. 2010 Feb 2;121(4):537-48
references.pmid: 20083679
references.citation: J Exp Med. 2009 May 11;206(5):1167-79
references.pmid: 19398754
references.citation: J Pharmacol Exp Ther. 2007 Apr;321(1):187-94
references.pmid: 17229879
references.citation: Circ Res. 1998 Sep 7;83(5):568-77
references.pmid: 9734480
references.citation: Antimicrob Agents Chemother. 2007 Dec;51(12):4303-7
references.pmid: 17923486
references.citation: J Pharmacol Exp Ther. 2006 Dec;319(3):1265-75
references.pmid: 16943253
references.citation: Diabetes. 2005 May;54(5):1400-6
references.pmid: 15855326
references.citation: Circ Res. 2008 Nov 21;103(11):1232-40
references.pmid: 18845810
references.citation: J Surg Res. 2007 May 1;139(1):128-35
references.pmid: 17292406
references.citation: FASEB J. 2005 Dec;19(14):2045-7
references.pmid: 16223783
references.citation: J Clin Invest. 1999 Apr;103(7):1047-54
references.pmid: 10194478
references.citation: Trends Immunol. 2003 Aug;24(8):449-55
references.pmid: 12909459
references.citation: Cancer Immunol Immunother. 2007 Nov;56(11):1807-15
references.pmid: 17440721
references.citation: J Exp Med. 2003 Dec 1;198(11):1707-16
references.pmid: 14657222