title: Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice.
abstract: Tissue factor (TF) is the primary activator of the coagulation cascade. During endotoxemia, TF expression leads to disseminated intravascular coagulation. However, the relative contribution of TF expression by different cell types to the activation of coagulation has not been defined. In this study, we investigated the effect of either a selective inhibition of TF expression or cell type-specific deletion of the TF gene (F3) on activation of coagulation in a mouse model of endotoxemia. We found that inhibition of TF on either hematopoietic or nonhematopoietic cells reduced plasma thrombin-antithrombin (TAT) levels 8 hours after administration of bacterial lipopolysaccharide (LPS). In addition, plasma TAT levels were significantly reduced in endotoxemic mice lacking the TF gene in either myeloid cells (TF(flox/flox),LysM(Cre) mice) or in both endothelial cells (ECs) and hematopoietic cells (TF(flox/flox),Tie-2(Cre) mice). However, deletion of the TF gene in ECs alone had no effect on LPS-induced plasma TAT levels. Similar results were observed in mice lacking TF in vascular smooth muscle cells. Finally, we found that mouse platelets do not express TF pre-mRNA or mRNA. Our data demonstrate that in a mouse model of endotoxemia activation of the coagulation cascade is initiated by TF expressed by myeloid cells and an unidentified nonhematopoietic cell type(s).
authors.affiliation: Hematology and Oncology Division, Department of Medicine, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Wang
authors.forename: A Phillip
authors.initials: AP
authors.lastname: Owens
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Silvio
authors.initials: S
authors.lastname: Antoniak
authors.forename: Michael
authors.initials: M
authors.lastname: Tencati
authors.forename: Thomas
authors.initials: T
authors.lastname: Luther
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Rowley
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Low
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Weyrich
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000032:analysis; D001777:Blood Coagulation / Q000502:physiology*; D001792:Blood Platelets / Q000378:metabolism; D002478:Cells, Cultured; D004211:Disseminated Intravascular Coagulation / Q000209:etiology / Q000503:physiopathology; D042783:Endothelial Cells / Q000378:metabolism; D019446:Endotoxemia / Q000097:blood / Q000503:physiopathology*; D017353:Gene Deletion; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000032:analysis; D012322:RNA Precursors / Q000096:biosynthesis / Q000097:blood; D012333:RNA, Messenger / Q000096:biosynthesis / Q000097:blood; D011828:Radiation Chimera; D013045:Species Specificity; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; D012322:RNA Precursors; D012333:RNA, Messenger; C046193:antithrombin III-protease complex; C440499:lipopolysaccharide, Escherichia coli O111 B4; D000990:Antithrombin III; D013925:Thromboplastin; D010447:Peptide Hydrolases
references.citation: Am J Pathol. 2005 Oct;167(4):1161-72
references.pmid: 16192650
references.citation: Am J Respir Crit Care Med. 1998 Jul;158(1):92-8
references.pmid: 9655712
references.citation: Arterioscler Thromb. 1992 Apr;12(4):474-83
references.pmid: 1348427
references.citation: Dev Biol. 2001 Feb 15;230(2):230-42
references.pmid: 11161575
references.citation: Blood. 2005 Mar 15;105(6):2350-5
references.pmid: 15522962
references.citation: Blood. 1998 Mar 1;91(5):1609-15
references.pmid: 9473226
references.citation: Am J Pathol. 1989 May;134(5):1087-97
references.pmid: 2719077
references.citation: Blood. 2005 Apr 1;105(7):2764-70
references.pmid: 15604222
references.citation: Mol Cell Biol. 1991 Sep;11(9):4732-8
references.pmid: 1875949
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17132-7
references.pmid: 15569937
references.citation: J Clin Invest. 1983 Jun;71(6):1893-6
references.pmid: 6345590
references.citation: Genesis. 2001 May;30(1):36-44
references.pmid: 11353516
references.citation: Blood. 2009 Jan 15;113(3):705-13
references.pmid: 18931346
references.citation: Lab Invest. 1997 Dec;77(6):581-9
references.pmid: 9426395
references.citation: J Thromb Haemost. 2006 Jun;4(6):1323-30
references.pmid: 16706978
references.citation: J Exp Med. 2006 Oct 30;203(11):2433-40
references.pmid: 17060476
references.citation: Blood. 2007 Feb 15;109(4):1503-6
references.pmid: 17032923
references.citation: Crit Care Clin. 2005 Jul;21(3):449-67
references.pmid: 15992667
references.citation: Blood. 2000 Jul 1;96(1):170-5
references.pmid: 10891447
references.citation: Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H873-85
references.pmid: 15833800
references.citation: Biochem Biophys Res Commun. 2001 Feb 23;281(2):603-9
references.pmid: 11181090
references.citation: Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1690-6
references.pmid: 12855480
references.citation: Arterioscler Thromb Vasc Biol. 1995 May;15(5):612-21
references.pmid: 7749875
references.citation: Thromb Res. 1988 Nov 1;52(3):247-61
references.pmid: 3194899
references.citation: Semin Thromb Hemost. 2006 Feb;32(1):11-23
references.pmid: 16479458
references.citation: J Thromb Haemost. 2007 Aug;5(8):1693-700
references.pmid: 17663739
references.citation: Mol Cell Biol. 2007 Nov;27(21):7683-92
references.pmid: 17724086
references.citation: Blood. 2008 Feb 1;111(3):1208-16
references.pmid: 17947506
references.citation: Blood. 2003 May 15;101(10):3940-7
references.pmid: 12543866
references.citation: Blood. 2007 Feb 1;109(3):995-1002
references.pmid: 17003379
references.citation: Blood. 2005 Sep 1;106(5):1604-11
references.pmid: 15741221
references.citation: Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1687-93
references.pmid: 17556654
references.citation: Mol Cell Biol. 1989 Jun;9(6):2752-5
references.pmid: 2503712
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1493-8
references.pmid: 15860742
references.citation: Am J Pathol. 1993 Jul;143(1):76-84
references.pmid: 8317556
references.citation: Blood. 2007 Jun 15;109(12):5242-50
references.pmid: 17347408
references.citation: J Exp Med. 1994 Apr 1;179(4):1253-9
references.pmid: 8145042
references.citation: Circ Shock. 1991 Mar;33(3):127-34
references.pmid: 2044206
references.citation: Transgenic Res. 1999 Aug;8(4):265-77
references.pmid: 10621974
references.citation: Blood Cells Mol Dis. 2004 Mar-Apr;32(2):325-33
references.pmid: 15003826
references.citation: Blood. 2000 Jul 15;96(2):554-9
references.pmid: 10887118
references.citation: Infect Immun. 1999 May;67(5):2540-6
references.pmid: 10225918
references.citation: Blood. 2004 Feb 15;103(4):1342-7
references.pmid: 14576054
references.citation: Development. 1996 Aug;122(8):2415-25
references.pmid: 8756287
references.citation: Thromb Haemost. 2000 Jun;83(6):861-7
references.pmid: 10896239
references.citation: Blood. 2009 Sep 17;114(12):2521-9
references.pmid: 19620400
references.citation: J Thromb Haemost. 2005 May;3(5):1098-9
references.pmid: 15869619
references.citation: Am J Pathol. 1993 May;142(5):1458-70
references.pmid: 7684196
references.citation: Eur Heart J. 2005 Apr;26(7):682-8
references.pmid: 15684280
references.citation: J Exp Med. 2008 Jun 9;205(6):1303-15
references.pmid: 18474628