title: Contribution of protein Z and protein Z-dependent protease inhibitor in generalized Shwartzman reaction.
abstract: OBJECTIVE
  Sepsis, a leading cause of mortality in critically ill patients, is closely linked to the excessive activation of coagulation and inflammation. Protein Z, a cofactor for the protein Z-dependent protease inhibitor, enhances the inhibition of coagulation factor Xa, and protein Z-dependent protease inhibitor inhibits factor XIa in a protein Z-independent fashion. The functions of protein Z and protein Z-dependent protease inhibitor in the inflammatory and coagulant responses to septic illness have not been evaluated.
  
  
  METHODS
  For induction of generalized Shwartzman reaction, dorsal skinfold chamber-equipped mice were challenged twice with lipopolysaccharide (0.05 mg/kg on day -1 and 5 mg/kg body weight 24 hr later). Time-matched control animals received equal volumes of saline.
  
  
  METHODS
  University research laboratory.
  Using intravital fluorescence microscopy in protein Z-dependent protease inhibitor deficient (ZPI) and protein Z deficient (PZ) mice, as well as their wild-type littermates (ZPI, PZ), kinetics of light/dye-induced thrombus formation and microhemodynamics were assessed in randomly chosen venules. Plasma concentrations of chemokine (C-X-C motif) ligand 1, interleukin-6, and interleukin-10 were measured. Liver and lung were harvested for quantitative analysis of leukocytic tissue infiltration and thrombus formation.
  
  
  RESULTS
  After induction of generalized Shwartzman reaction, all mice showed significant impairment of microhemodynamics, including blood flow velocity, volumetric blood flow, and functional capillary density, as well as leukocytopenia and thrombocytopenia. Thrombus formation time was markedly prolonged after induction of generalized Shwartzman reaction in all mice, except of ZPI mice, which also had a significantly higher fraction of occluded vessels in liver sections. PZ mice developed the highest concentrations of interleukin-6 and interleukin-10 in response to generalized Shwartzman reaction and showed greater leukocytic tissue infiltration than their wild-type littermates.
  
  
  CONCLUSIONS
  In this murine model of generalized Shwartzman reaction, protein Z-dependent protease inhibitor deficiency enhanced the thrombotic response to vascular injury, whereas protein Z deficiency increased inflammatory response.
authors: 1Institute for Experimental Surgery, University of Rostock, Rostock, Germany. 2Division of Hematology, Washington University Medical Center, St. Louis, MO.
authors: Antje
authors: A
authors: Butschkau
authors: Philipp
authors: P
authors: Nagel
authors: Eberhard
authors: E
authors: Grambow
authors: Dietmar
authors: D
authors: Zechner
authors: George J
authors: GJ
authors: Broze
authors: Brigitte
authors: B
authors: Vollmar
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity; D001798:Blood Proteins / Q000235:genetics / Q000502:physiology*; D054360:Chemokine CXCL1 / Q000097:blood; D005838:Genotype; D007375:Interleukin-1 / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D007970:Leukopenia / Q000097:blood; D008070:Lipopolysaccharides; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015843:Serpins / Q000235:genetics / Q000502:physiology*; D012790:Shwartzman Phenomenon / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D013921:Thrombocytopenia / Q000097:blood; D013927:Thrombosis / Q000097:blood / Q000209:etiology; D014699:Venules / Q000502:physiology
chemical_list: D001798:Blood Proteins; D054360:Chemokine CXCL1; D007375:Interleukin-1; D008070:Lipopolysaccharides; C485937:Serpina10 protein, mouse; D015843:Serpins; C026080:plasma protein Z; D016753:Interleukin-10
references: Biochem Soc Trans. 1977;5(1):255-6
references: 892175
references: Br J Haematol. 2004 Oct;127(2):190-4
references: 15461625
references: Blood. 2000 Nov 1;96(9):3049-55
references: 11049983
references: Chest. 1992 Mar;101(3):816-23
references: 1531791
references: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9250-5
references: 9689066
references: Crit Care Med. 2006 Feb;34(2):285-92
references: 16424704
references: Expert Opin Biol Ther. 2007 Jun;7(6):855-70
references: 17555371
references: Lancet. 2001 Mar 24;357(9260):933-4
references: 11289354
references: Am J Pathol. 1993 Oct;143(4):1055-62
references: 7692730
references: Hamostaseologie. 2011 May 2;31(2):94-102, 104
references: 21152678
references: J Surg Res. 1990 Aug;49(2):186-96
references: 2199735
references: Cell. 1991 Dec 20;67(6):1033-6
references: 1760836
references: Crit Care Med. 2002 Jan;30(1):218-25
references: 11902265
references: Thromb Haemost. 2005 Mar;93(3):411-3
references: 15735788
references: Thromb J. 2006 Aug 24;4:13
references: 16930474
references: Thromb Haemost. 2002 Feb;87(2):350-1
references: 11858503
references: Thromb Haemost. 2010 Apr;103(4):749-56
references: 20076855
references: J Leukoc Biol. 2007 Jan;81(1):137-43
references: 17020929
references: Thromb Haemost. 2001 Jul;86(1):8-13
references: 11487045
references: J Thromb Haemost. 2009 May;7(5):731-5
references: 19228280
references: Thromb Res. 1999 Apr 15;94(2):131-4
references: 10230898
references: N Engl J Med. 2001 Mar 8;344(10):699-709
references: 11236773
references: Brain Struct Funct. 2010 Mar;214(2-3):91-109
references: 19937345
references: Br J Haematol. 2007 Apr;137(2):99-108
references: 17391489
references: Thromb Haemost. 2006 Mar;95(3):519-23
references: 16525581
references: Microvasc Res. 1974 Jan;7(1):131-43
references: 4821168
references: J Biol Chem. 2005 Oct 7;280(40):33819-25
references: 16093243
references: Clin Chest Med. 2008 Dec;29(4):617-25, viii
references: 18954697
references: Crit Care. 2005;9 Suppl 4:S13-9
references: 16168069
references: Blood. 2008 May 15;111(10):4973-8
references: 18344422
references: Crit Care Med. 2004 Apr;32(4):1011-7
references: 15071394
references: Biochemistry. 2006 Aug 8;45(31):9427-33
references: 16878977
references: Thromb Haemost. 2001 Apr;85(4):655-60
references: 11341501
references: J Leukoc Biol. 2005 Jan;77(1):3-15
references: 15522916
references: Pflugers Arch. 2010 Mar;459(4):557-67
references: 20140450
references: Crit Care. 2004 Dec;8(6):462-8
references: 15566617
references: Biochemistry. 1999 Aug 24;38(34):11073-8
references: 10460162
references: Surgery. 2012 Jan;151(1):26-36
references: 22019501
references: Biochemistry. 1998 May 12;37(19):6838-46
references: 9578570
references: Blood Coagul Fibrinolysis. 2007 Jan;18(1):85-6
references: 17179834
references: J Leukoc Biol. 2010 Mar;87(3):501-8
references: 20007247
references: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6734-8
references: 10829076
references: Thromb Haemost. 2001 Jan;85(1):160-4
references: 11204568
references: J Clin Invest. 1984 Apr;73(4):933-8
references: 6707212
references: J Thromb Haemost. 2006 Nov;4(11):2417-22
references: 16938126
references: Lancet. 2006 Jul 8;368(9530):157-69
references: 16829300
references: Minerva Anestesiol. 2010 Oct;76(10):851-9
references: 20935621