Impaired wound healing in factor XIII deficient mice

Amir Inbal; Aharon Lubetsky; Tanya Krapp; David Caste; Aviv Shaish; Gerhardt Dickneitte; Laszlo Modis; Laszlo Muszbek; Aida Inbal

doi:10.1160/TH05-04-0291

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 94(02): 432-437
DOI: 10.1160/TH05-04-0291

Wound Healing and Inflammation/Infection

Schattauer GmbH

Impaired wound healing in factor XIII deficient mice

Amir Inbal^*

¹Institutes of Thrombosis and Hemostasis, Tel Aviv University, Israel

,

Aharon Lubetsky^*

¹Institutes of Thrombosis and Hemostasis, Tel Aviv University, Israel

,

Tanya Krapp

¹Institutes of Thrombosis and Hemostasis, Tel Aviv University, Israel

,

David Caste

¹Institutes of Thrombosis and Hemostasis, Tel Aviv University, Israel

²Institutes of Cardiology Research, Tel Aviv University, Israel

,

Aviv Shaish

³Institutes of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel

,

Gerhardt Dickneitte

⁴Pharmacology and Toxicology, ZLB-Behring, Marburg, Germany

,

Laszlo Modis

⁵Department of Anatomy Histology and Embryology, University of Debrecen

,

Laszlo Muszbek

⁶Medical and Health Science Center, Clinical Research Center and Thrombosis and Hemostasis Research Group of the Hungarian Academy of Sciences, University of Debrecen, Debrecen, Hungary

,

Aida Inbal

¹Institutes of Thrombosis and Hemostasis, Tel Aviv University, Israel

› Institutsangaben

Abstract

Summary

Factor XIII that stabilizes fibrin clots in the final stages of blood coagulation also participates in wound healing,as can be inferred from a delay in wound repair in some patients with inherited FXIII deficiency. In this study we evaluated the effect of FXIII on wound healing in FXIII-deficient mice. Three groups of mice (n = 10) were employed: control group, FXIII-deficient group and FXIII-deficient group treated with FXIII concentrate. Excisional wounds were left unsutured and undressed, and mice were followed for eleven days. FXIII-deficient mice exhibited impaired wound healing as has been demonstrated by 15%, 27% and 27% decrease in percentage of wound closure on day 4, 8 and 11, respectively. On day 11 complete healing was observed in control (100% closure), 73.23% in FXIII-deficient and 90.06% in FXIII deficient/FXIII-treated groups (p = 0.007 by ANOVA and p = 0.001 by t-test between control and FXIII-deficient groups). Scoring system representing maturation rate of the wounds showed that the scores for the control,FXIII-deficient and FXIIIdeficient/ FXIII treated groups were 94.9 ± 4.7, 61.5 ± 14.5 and 94.5 ± 6.4, respectively (p < 0.001 by ANOVA). Histological analysis of the lesions performed at day 11 disclosed delayed reepithelization and necrotized fissure in FXIII-deficient mice and normal healing in FXIII-deficient/FXIII-treated mice. The findings of this study confirm that in FXIII-deficient mice wound healing is delayed and the cellular and tissue defects can be corrected by treatment with FXIII, providing evidence for the essential role of FXIII in wound repair and remodeling.

Keywords

FXIII - FXIII-deficient mice - wound healing

Volltext

Referenzen

References
1 Verderion EAM, Johnson T, Griffin M. Tissue transglutaminase in normal and abnormal wound healing: Review article. Amino Acids 2004; 26: 387-404.
2 Romer J, Bugge TH, Pyke C. et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med 1996; 2: 287-92.
3 Te Velde EAT, Wagenaar GTM, Reijerkerk A. et al. Impaired healing of cutaneous wounds and colonic anastomoses in mice lacking thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost 2003; 1: 2087-96.
4 Drew AF, Liu H, Davidson JM. et al. Wound-healing defects in mice lacking fibrinogen. Blood 2001; 97: 3691-8.
5 Chan JC, Duszezyszyn DA, Sastellino FJ. et al. Accelerated skin wound healing in plasminogen activator inhibitor-1-deficient mice. Am J Pathol 2001; 159: 1681-8.
6 Muszbek L, Adany R, Mikkola H. Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation and function. Crit Rev Clin Lab Sci 1996; 33: 357-421.
7 Nagy JA, Kradin RL, Mc Donagh J. Biosynthesis of factor FXIII A and B subunits. Adv Exp Med Bio 1988; 231: 29-49.
8 Procyk R, Blomback B. Factor XIII-induced crosslinking in solutions of fibrinogen and fibronectin. Biochim Biophys Acta 1988; 967: 304-13.
9 Hada M, Kaminski M, Bockenstedt P. et al. Covalent crosslinking of von Willebrand factor to fibrin. Blood 1986; 68: 95-101.
10 Sane DC, Moser TL, Pippen AM. et al. Vitronectin is a substrate for transglutaminases. Biochem Biophys Res Commun 1988; 157: 115-20.
11 Prince CW, Dickie D, Krumdieck CL. Osteopontin, a substrate for transglutaminase and factor XIII activity. Biochem Biophys Res Commun 1991; 177: 1205-10.
12 Lynch GW, Slayter HS, Miller BE. et al.. Characterization of thrombospondin as a substrate for factor XIII transglutaminase. J Biol Chem 1987; 262: 1772-8.
13 Becker SWJ, Weidt F, Rohl K. The role of plasma transglutaminase (FXIII) in wound healing of complicated pressure after spinal cord injury. Spinal Cord 2001; 39: 114-7.
14 Wozniak G, Dapper F, Alemany J. Factor FXIII in ulcerative leg disease: Background and preliminary clinical results. Sem Thromb Hemost 1996; 22: 445-50.
15 Grothaus-Pinke B, Gunzelmann S, Fauser AA. et al. Factor XIII replacement in stem cell transplant (SCT) recipients with severe graft-versus-host disease of the bowel: report of an initial experimance. Transplantation 2001; 72: 1456-8.
16 Claes L, Burri C, Gerngross H. et al. Bone healing stimulated by plasma factor XIII. Acta Orthop Scand 1985; 56: 57-62.
17 Ogawa T, Morioka Y, Inoue T. et al. Involvement of blood coagulation factor XIII in burn healing in the carbon tetrachloride-induced hepatic injury model in rats. Inflamm Res 1995; 44: 264-8.
18 Lanir N, Ciano PS, Van de Water L. et al.. Macrophage migration in fibrin gel matrices. II. Effects of clotting factor XIII, fibronectin, and glycosaminoglycan content on cell migration. J Immunol 1988; 140: 2340-9.
19 Sarvary A, Szucs S, Balogh I. et al. Possible role of factor XIII subunit A in Fcgamma and complement receptor- mediated phagocytosis. Cell Immunol 2004; 228: 1-90.
20 Barry EL, Mosher DF. Binding and degradation of blood coagulation factor XIII by cultured fibroblasts. J Biol Chem 1990; 265: 9302-7.
21 Dardik R, Solomon A, Loscalzo J. et al. Novel proangiogenic effect of factor XIII (FXIII) associated with suppression of thrombospondin1 (TSP-1) expression. Arteriosc Thromb Vasc Biol 2003; 23: 1472-7.
22 Lauer P, Metzner HJ, Zettlmeibl G. et al. Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: Hemostatic abnormalities in mutant mice and characterization of the coagulation deficit. Thromb Haemost 2002; 88: 967-74.
23 Constantine VS, Mowry RW. Selective staining of human dermal collagen. II. The use of picrosirius red F3BA with polarization microscopy. J Invest Dermatol 1968; 50: 419-23.
24 Módis L. >The organization of the extracellular matrix.. CRC Press; Boca Raton: 1991
25 Haroon ZA, Hettasch JM, Lai TS. et al. Tissue transglutaminase is expressed, active, and directly involved in rat dermal wound healing and angiogenesis. FASEB 1999; 13: 1787-95.
26 Singer AJ, Clark RA. Cutaneous wound healing. New Engl J Med 1999; 341: 738-46.
27 Aeschlimann D, Thommazy Y. Protein crosslinking in assembly and remodelling of extracellular matrices: The role of transglutaminases. Connect Tissue Res 2000; 41: 1-27.
28 Valnickova S, Enghild JJ. Human procarboxypeptidase U, or thrombin-activable fibrinolysis inhibitor is a substrate for transglutaminases. Evidence for transglutaminase- catalysed cross-linking to fibrin. J Biol Chem 1998; 273: 27220-4.
29 Bryant M, Drew GM, Houston P. et al. Tissue repair with a therapeutic transcription factor. Hum Gene Ther 2000; 11: 2143-58.