title: Factor VII deficiency impairs cutaneous wound healing in mice.
abstract: Skin keratinocytes express tissue factor (TF) and are highly associated with skin wound healing. Although it has been demonstrated that perivascular TF expression in granulation tissue formed after dermal injury is downregulated during healing, studies of the mechanism of factor (F) VII, a TF ligand, in skin wound healing are lacking. We reported the use of a dermal punch model to demonstrate that low-expressing FVII mice (approximately 1% of wild type [WT]) exhibited impaired skin wound healing compared with WT controls. These low-FVII mice showed defective reepithelialization and reduced inflammatory cell infiltration at wound sites. This attenuated reepithelialization was associated with diminished expression of the transcription factor early growth response 1 (Egr-1). In vitro, Egr-1 was shown to be essential for the FVIIa-induced regulation of keratinocyte migration and inflammation. Both Egr-1 upregulation and downstream inflammatory cytokine appearance in keratinocytes depended on FVIIa/TF/protease-activated receptor 2 (PAR-2)-induced signaling and did not require subsequent generation of FXa and thrombin. The participation of Egr-1 in FVIIa-mediated regulation of keratinocyte function was confirmed by use of Egr-1-deficient mice, wherein a significant delay in skin wound healing after injury was observed, relative to WT mice. The results from these studies demonstrate an in vivo mechanistic relationship between FVIIa, Egr-1 and the inflammatory response in keratinocyte function during the wound healing process.
authors.affiliation: WM Keck Center for Transgene Research and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States of America.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.forename: Haifeng
authors.initials: H
authors.lastname: Xu
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Ploplis
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
mesh_terms: D000818:Animals; D002465:Cell Movement; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005167:Factor VII / Q000235:genetics / Q000378:metabolism*; D005168:Factor VII Deficiency / Q000503:physiopathology*; D006651:Histocytochemistry; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D044464:Receptor, PAR-2 / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D013864:Thioglycolates; D013925:Thromboplastin / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D044464:Receptor, PAR-2; D013864:Thioglycolates; D005167:Factor VII; D013925:Thromboplastin
references.citation: Science. 1983 May 13;220(4598):728-31
references.pmid: 6836310
references.citation: Proc Biol Sci. 1996 May 22;263(1370):653-60
references.pmid: 8677263
references.citation: J Invest Dermatol. 2008 Aug;128(8):2092-101
references.pmid: 18337830
references.citation: EMBO J. 1999 Sep 1;18(17):4645-56
references.pmid: 10469644
references.citation: J Invest Dermatol. 2007 May;127(5):998-1008
references.pmid: 17435785
references.citation: Blood. 2002 Feb 1;99(3):1053-9
references.pmid: 11807012
references.citation: Int Rev Cytol. 2007;257:143-79
references.pmid: 17280897
references.citation: Circulation. 2004 Jun 15;109(23):2911-6
references.pmid: 15173027
references.citation: Blood. 2008 Feb 15;111(4):2046-8
references.pmid: 18055866
references.citation: Diabetes. 2005 Jul;54(7):2143-54
references.pmid: 15983216
references.citation: J Invest Dermatol. 2003 Feb;120(2):335-43
references.pmid: 12542542
references.citation: Nat Med. 2004 May;10(5):502-9
references.pmid: 15098027
references.citation: Am J Surg. 1998 Aug;176(2A Suppl):26S-38S
references.pmid: 9777970
references.citation: Ann Med. 2001 Jul;33(5):313-8
references.pmid: 11491188
references.citation: Blood. 2006 Nov 1;108(9):3053-60
references.pmid: 16825491
references.citation: Int Immunopharmacol. 2004 Dec 20;4(14):1873-80
references.pmid: 15531302
references.citation: J Clin Invest. 1998 Feb 1;101(3):560-9
references.pmid: 9449688
references.citation: Thromb Haemost. 2005 Sep;94(3):493-7
references.pmid: 16268461
references.citation: Am J Pathol. 2006 Dec;169(6):2254-65
references.pmid: 17148686
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5255-60
references.pmid: 10805786
references.citation: Thromb Haemost. 2004 Jul;92(1):13-22
references.pmid: 15213840
references.citation: EMBO J. 2006 Jun 21;25(12):2686-97
references.pmid: 16763560
references.citation: J Clin Invest. 1998 Apr 1;101(7):1372-8
references.pmid: 9525979
references.citation: J Clin Oncol. 2009 Oct 10;27(29):4834-8
references.pmid: 19738116
references.citation: Exp Cell Res. 2005 Mar 10;304(1):274-86
references.pmid: 15707592
references.citation: Exp Dermatol. 2006 Jul;15(7):523-9
references.pmid: 16761961
references.citation: Am J Pathol. 2001 Nov;159(5):1681-8
references.pmid: 11696429
references.citation: Blood. 2004 Apr 15;103(8):3029-37
references.pmid: 15070680
references.citation: Crit Rev Clin Lab Sci. 1996;33(5):357-421
references.pmid: 8922891
references.citation: Eur J Surg. 1999 Nov;165(11):1012-9
references.pmid: 10595602
references.citation: Australas J Dermatol. 1996 May;37 Suppl 1:S48-9
references.pmid: 8713017
references.citation: Thromb Haemost. 2004 Aug;92(2):275-80
references.pmid: 15269822
references.citation: Am J Pathol. 2009 Sep;175(3):1041-55
references.pmid: 19679873
references.citation: Thromb Haemost. 2005 Aug;94(2):432-7
references.pmid: 16113836
references.citation: J Pathol. 2006 Dec;210(4):488-96
references.pmid: 17054310
references.citation: J Thromb Haemost. 2007 Aug;5(8):1588-97
references.pmid: 17470200
references.citation: Hum Gene Ther. 2000 Oct 10;11(15):2143-58
references.pmid: 11044915
references.citation: Nat Med. 1996 Mar;2(3):287-92
references.pmid: 8612226
references.citation: Thromb Res. 2008;122 Suppl 1:S73-7
references.pmid: 18691506
references.citation: Am J Pathol. 2007 Mar;170(3):818-29
references.pmid: 17322368
references.citation: Wound Repair Regen. 2007 Jan-Feb;15(1):23-34
references.pmid: 17244316
references.citation: Nature. 1997 Nov 20;390(6657):290-4
references.pmid: 9384381
references.citation: Blood. 2003 Dec 1;102(12):3998-4005
references.pmid: 12920028
references.citation: J Thromb Haemost. 2007 Aug;5(8):1577-83
references.pmid: 17663728
references.citation: Science. 1996 Mar 8;271(5254):1427-31
references.pmid: 8596917
references.citation: J Invest Dermatol. 2001 Dec;117(6):1382-90
references.pmid: 11886498
references.citation: J Biol Chem. 2000 Mar 3;275(9):6580-5
references.pmid: 10692465
references.citation: Nature. 2006 May 18;441(7091):362-5
references.pmid: 16710422
references.citation: Nat Med. 2003 Aug;9(8):1026-32
references.pmid: 12872165
references.citation: Nature. 2001 Sep 6;413(6851):74-8
references.pmid: 11544528
references.citation: Blood. 2004 Feb 15;103(4):1342-7
references.pmid: 14576054
references.citation: Am J Pathol. 1998 Oct;153(4):1035-9
references.pmid: 9777935
references.citation: J Immunol. 2006 Mar 15;176(6):3780-7
references.pmid: 16517748
references.citation: Lab Invest. 1983 Dec;49(6):702-7
references.pmid: 6317983