title: Cell-free hemoglobin and its scavenger proteins: new disease models leading the way to targeted therapies.
abstract: Hemoglobin (Hb) has multiple pathophysiologic effects when released into the intravascular space during hemolysis. The extracellular effects of Hb have resulted in novel models of toxicity, which help to explain endothelial dysfunction and cardiovascular complications that accompany genetic hemolytic anemias, malaria, blood transfusion, and atherosclerosis. The majority of models focus on nitric oxide (NO) depletion; however, in local tissue environments, Hb can also act as a pro-oxidant and inflammatory agent. This can alter cellular differentiation with the potential to deviate immune responses. The understanding of these mechanisms set in the context of natural scavenger and detoxification systems may accelerate the development of novel treatment strategies.
authors: Division of Internal Medicine, University Hospital, Zurich CH-8091, Switzerland. dominik.schaer@usz.ch
authors: Dominik J
authors: DJ
authors: Schaer
authors: Paul W
authors: PW
authors: Buehler
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000628:therapy; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood; D017707:Erythrocyte Transfusion; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism*; D006461:Hemolysis; D006466:Hemopexin / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology; D008288:Malaria / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D011956:Receptors, Cell Surface / Q000378:metabolism; D051116:Receptors, Scavenger / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D006454:Hemoglobins; D011956:Receptors, Cell Surface; D051116:Receptors, Scavenger; D009569:Nitric Oxide; D006466:Hemopexin; D006419:Heme Oxygenase (Decyclizing)
references: Free Radic Biol Med. 2008 Oct 15;45(8):1150-8
references: 18708138
references: J Clin Invest. 1999 Jan;103(1):129-35
references: 9884342
references: Circ Res. 2006 Oct 27;99(9):943-50
references: 17008602
references: J Biol Chem. 2007 Feb 16;282(7):4894-4907
references: 17178725
references: J Clin Invest. 2009 Aug;119(8):2271-80
references: 19620788
references: N Engl J Med. 2011 Dec 29;365(26):2532-3
references: 22168589
references: N Engl J Med. 2004 Feb 26;350(9):886-95
references: 14985486
references: J Neuroinflammation. 2012 Mar 06;9:46
references: 22394415
references: J Clin Invest. 2012 Apr;122(4):1205-8
references: 22446184
references: J Emerg Med. 1994 Jan-Feb;12(1):33-7
references: 8163802
references: Anesthesiology. 2009 Jan;110(1):113-22
references: 19104178
references: N Engl J Med. 2011 Jul 7;365(1):44-53
references: 21732836
references: Shock. 1998 Dec;10(6):401-6
references: 9872678
references: N Engl J Med. 2004 Oct 14;351(16):1655-65
references: 15483284
references: Hematology Am Soc Hematol Educ Program. 2011;2011:466-9
references: 22160075
references: Am J Physiol. 1989 Mar;256(3 Pt 2):F446-55
references: 2923223
references: Nat Med. 2002 Dec;8(12):1383-9
references: 12426562
references: Anesthesiology. 2012 Jul;117(1):56-63
references: 22531338
references: Transfusion. 2012 Jun;52(6):1184-95
references: 22188419
references: Nat Med. 2011 Dec 18;18(1):120-7
references: 22179318
references: Am J Respir Crit Care Med. 2011 Apr 1;183(7):922-31
references: 20971829
references: J Clin Invest. 2012 Apr;122(4):1444-58
references: 22446185
references: Blood. 2003 May 15;101(10):3953-9
references: 12543857
references: Blood. 2002 Aug 1;100(3):879-87
references: 12130498
references: Anesthesiology. 2009 Nov;111(5):946-63
references: 19858869
references: Blood. 2010 May 27;115(21):4284-92
references: 20299509
references: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2699-704
references: 20133658
references: Blood. 2011 Dec 15;118(25):6675-82
references: 22021369
references: Nitric Oxide. 2012 Jun 30;27(1):32-9
references: 22521791
references: J Biol Chem. 1998 Nov 27;273(48):31731-7
references: 9822635
references: J Leukoc Biol. 2010 Dec;88(6):1201-5
references: 20807704
references: N Engl J Med. 2003 Dec 11;349(24):2316-25
references: 14668457
references: Protein Sci. 2011 May;20(5):791-805
references: 21404362
references: Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1347-53
references: 20378845
references: JAMA. 2005 Apr 6;293(13):1653-62
references: 15811985
references: J Am Coll Cardiol. 2012 Jan 10;59(2):166-77
references: 22154776
references: Sci Transl Med. 2010 Sep 29;2(51):51ra71
references: 20881280
references: Antioxid Redox Signal. 2010 Feb;12(2):181-4
references: 19788393
references: Am J Physiol Heart Circ Physiol. 2003 Jan;284(1):H81-91
references: 12388216
references: N Engl J Med. 2011 Jun 30;364(26):2549-51
references: 21714653
references: Antioxid Redox Signal. 2010 Feb;12(2):305-20
references: 19650691
references: Circulation. 2011 Jul 26;124(4):465-76
references: 21747051
references: Pharmacol Rev. 2008 Mar;60(1):79-127
references: 18323402
references: J Proteome Res. 2011 May 6;10(5):2397-408
references: 21405025
references: Biochemistry. 1997 Oct 7;36(40):12189-98
references: 9315856
references: Eur J Haematol. 2005 Jan;74(1):6-10
references: 15613100
references: Circ Res. 2012 Jan 6;110(1):20-33
references: 22052915
references: Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9285-9
references: 8415693
references: J Infect Dis. 2010 Aug 15;202(4):624-32
references: 20617898
references: Antioxid Redox Signal. 2010 Feb;12(2):293-304
references: 19659435
references: Blood. 2009 Mar 12;113(11):2578-86
references: 19131549
references: Trends Mol Med. 2010 Oct;16(10):447-57
references: 20708968
references: Transfusion. 2012 Jul;52(7):1410-22
references: 22233290
references: J Clin Invest. 2005 Dec;115(12):3409-17
references: 16294219
references: Nat Rev Drug Discov. 2004 Feb;3(2):152-9
references: 15043006
references: Nat Med. 2006 Dec;12(12):1417-22
references: 17099710
references: Nat Med. 2007 Jun;13(6):703-10
references: 17496899
references: Nat Biotechnol. 1998 Jul;16(7):672-6
references: 9661203
references: Circulation. 2008 Apr 15;117(15):1982-90
references: 18391111
references: Am J Pathol. 2009 Mar;174(3):1097-108
references: 19234137
references: J Leukoc Biol. 2007 Jul;82(1):106-10
references: 17460152
references: Am J Physiol Heart Circ Physiol. 2002 Oct;283(4):H1292-301
references: 12234778
references: Cell. 2011 Apr 29;145(3):398-409
references: 21529713
references: Free Radic Biol Med. 2004 Mar 15;36(6):685-97
references: 14990349
references: Blood. 2001 Dec 1;98(12):3315-23
references: 11719369
references: J Proteome Res. 2010 Aug 6;9(8):4061-70
references: 20568812
references: Blood. 2006 Jan 1;107(1):373-80
references: 16189277
references: J Pharmacol Exp Ther. 2007 Oct;323(1):49-60
references: 17622572
references: Antioxid Redox Signal. 2010 Feb;12(2):199-208
references: 19659432
references: Anesthesiology. 2012 Mar;116(3):637-47
references: 22293717
references: Antioxid Redox Signal. 2010 Feb;12(2):249-59
references: 19650711
references: JAMA. 2008 May 21;299(19):2304-12
references: 18443023
references: Blood. 1999 Dec 1;94(11):3906-14
references: 10572107
references: Transfus Med Rev. 2013 Jan;27(1):36-43
references: 22902231
references: Nature. 2001 Jan 11;409(6817):198-201
references: 11196644
references: Trends Immunol. 2003 Aug;24(8):449-55
references: 12909459
references: Blood. 2010 Aug 5;116(5):687-92
references: 20395414
references: Antioxid Redox Signal. 2010 Feb;12(2):261-73
references: 19659436
references: Blood. 2010 Dec 9;116(24):5347-56
references: 20739658