title: Nucleosomes and neutrophil activation in sickle cell disease painful crisis.
abstract: Activated polymorphonuclear neutrophils play an important role in the pathogenesis of vaso-occlusive painful sickle cell crisis. Upon activation, polymorphonuclear neutrophils can form neutrophil extracellular traps. Neutrophil extracellular traps consist of a meshwork of extracellular DNA, nucleosomes, histones and neutrophil proteases. Neutrophil extracellular traps have been demonstrated to be toxic to endothelial and parenchymal cells. This prospective cohort study was conducted to determine neutrophil extracellular trap formation in sickle cell patients during steady state and painful crisis. As a measure of neutrophil extracellular traps, plasma nucleosomes levels were determined and polymorphonuclear neutrophil activation was assessed measuring plasma levels of elastase-α1-antitrypsin complexes in 74 patients in steady state, 70 patients during painful crisis, and 24 race-matched controls using Enzyme Linked Immunosorbent Assay. Nucleosome levels in steady state sickle cell patients were significantly higher than levels in controls. During painful crisis levels of both nucleosomes and elastase-α1-antitrypsin complexes increased significantly. Levels of nucleosomes correlated significantly to elastase-α1-antitrypsin complex levels during painful crisis, (Sr = 0.654, P<0.001). This was seen in both HbSS/HbSβ(0)-thalassemia (Sr=0.55, P<0.001) and HbSC/HbSβ(+-)thalassemia patients (Sr=0.90, P<0.001) during painful crisis. Levels of nucleosomes showed a correlation with length of hospital stay and were highest in patients with acute chest syndrome. These data support the concept that neutrophil extracellular trap formation and neutrophil activation may play a role in the pathogenesis of painful sickle cell crisis and acute chest syndrome.
authors.affiliation: s.s.zeerleder@amc.uva.nl.
authors.forename: Marein
authors.initials: M
authors.lastname: Schimmel
authors.forename: Erfan
authors.initials: E
authors.lastname: Nur
authors.forename: Bart J
authors.initials: BJ
authors.lastname: Biemond
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: van Mierlo
authors.forename: Shabnam
authors.initials: S
authors.lastname: Solati
authors.forename: Dees P
authors.initials: DP
authors.lastname: Brandjes
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Otten
authors.forename: John-John
authors.initials: JJ
authors.lastname: Schnog
authors.forename: Sacha
authors.initials: S
authors.lastname: Zeerleder
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018375:Neutrophil Activation / Q000502:physiology*; D009707:Nucleosomes / Q000378:metabolism*; D010146:Pain / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology*; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D009707:Nucleosomes
references.citation: Am J Physiol Heart Circ Physiol. 2006 Oct;291(4):H1679-85
references.pmid: 16714363
references.citation: J Exp Med. 2012 Apr 9;209(4):819-35
references.pmid: 22451716
references.citation: Blood. 2012 Aug 9;120(6):1157-64
references.pmid: 22611154
references.citation: Am J Hematol. 1982 Aug;13(1):37-51
references.pmid: 7137165
references.citation: Br J Haematol. 2008 Jun;141(6):872-81
references.pmid: 18422998
references.citation: FEBS Lett. 2010 Jul 16;584(14):3193-7
references.pmid: 20541553
references.citation: Medicine (Baltimore). 1996 Nov;75(6):300-26
references.pmid: 8982148
references.citation: Blood Cells Mol Dis. 2011 Mar 15;46(3):189-94
references.pmid: 21256776
references.citation: Nat Med. 2009 Apr;15(4):384-91
references.pmid: 19305412
references.citation: Am J Hematol. 2011 Jun;86(6):484-9
references.pmid: 21544855
references.citation: Br J Haematol. 1994 Jul;87(3):586-91
references.pmid: 7993801
references.citation: Crit Care Med. 2001 Jul;29(7):1404-7
references.pmid: 11445697
references.citation: FASEB J. 2008 Dec;22(12):4077-84
references.pmid: 18753248
references.citation: Nat Med. 2010 Aug;16(8):887-96
references.pmid: 20676107
references.citation: Blood. 2012 Oct 4;120(14):2879-88
references.pmid: 22833547
references.citation: Am J Respir Crit Care Med. 2012 Jun 1;185(11):1154-65
references.pmid: 22447965
references.citation: Nat Rev Microbiol. 2007 Aug;5(8):577-82
references.pmid: 17632569
references.citation: Arterioscler Thromb Vasc Biol. 2013 Jan;33(1):147-51
references.pmid: 23104849
references.citation: Pathol Int. 2011 May;61(5):290-7
references.pmid: 21501295
references.citation: Crit Care Med. 2012 Dec;40(12):3224-9
references.pmid: 22932399
references.citation: Eur J Haematol. 1998 Apr;60(4):267-8
references.pmid: 9579883
references.citation: PLoS One. 2012;7(2):e32366
references.pmid: 22389696
references.citation: Int J Infect Dis. 2012 Jul;16(7):e558-64
references.pmid: 22609014
references.citation: Blood. 2004 Mar 15;103(6):2397-400
references.pmid: 14630831
references.citation: N Engl J Med. 1994 Jun 9;330(23):1639-44
references.pmid: 7993409
references.citation: Blood. 1998 Jan 1;91(1):266-74
references.pmid: 9414294
references.citation: Pediatr Blood Cancer. 2012 Mar;58(3):399-405
references.pmid: 21793188
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3047-51
references.pmid: 11880644
references.citation: J Leukoc Biol. 1999 Sep;66(3):411-5
references.pmid: 10496310
references.citation: Science. 2004 Mar 5;303(5663):1532-5
references.pmid: 15001782
references.citation: Blood. 2008 Jan 15;111(2):915-23
references.pmid: 17932253
references.citation: Ann Rheum Dis. 2003 Jan;62(1):10-4
references.pmid: 12480662
references.citation: Eur J Haematol. 2000 Sep;65(3):155-64
references.pmid: 11007050
references.citation: J Exp Med. 2007 Apr 16;204(4):793-804
references.pmid: 17389238
references.citation: Br J Haematol. 2007 Oct;139(2):331-6
references.pmid: 17897311
references.citation: Blood. 1994 Jul 15;84(2):643-9
references.pmid: 7517723
references.citation: Arthritis Rheum. 1999 May;42(5):833-43
references.pmid: 10323438
references.citation: Crit Care Med. 2003 Jul;31(7):1947-51
references.pmid: 12847387
references.citation: J Lab Clin Med. 1992 Feb;119(2):159-68
references.pmid: 1740629
references.citation: N Engl J Med. 1991 Jul 4;325(1):11-6
references.pmid: 1710777
references.citation: Ann Intern Med. 2011 Sep 6;155(5):ITC31-15; quiz ITC316
references.pmid: 21893620
references.citation: Nat Med. 2009 Nov;15(11):1318-21
references.pmid: 19855397
references.citation: Blood. 1998 Jan 1;91(1):288-94
references.pmid: 9414296
references.citation: Am J Hematol. 2004 Jun;76(2):126-33
references.pmid: 15164377
references.citation: Eur J Haematol. 2002 Sep;69(3):135-44
references.pmid: 12406006
references.citation: Am J Hematol. 2002 Jul;70(3):206-15
references.pmid: 12111766
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15880-5
references.pmid: 20798043
references.citation: Blood. 1996 May 15;87(10):4440-7
references.pmid: 8639806