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Recombinant Factor XIII Improves Established Experimental Colitis in Rats

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Abstract

Factor XIII (FXIII) is the plasma-borne transglutaminase involved in fibrin clot stabilization and wound healing. FXIII levels in the plasma of patients with inflammatory bowel diseases are lower than normal and there is a significant inverse correlation of FXIII levels with clinical severity. Moreover, uncontrolled studies report beneficial effects of FXIII supplementation in patients resistant to conventional therapies. We investigated the effects of intravenous recombinant FXIII (rFXIII) treatment in experimentally induced rat colitis to verify that FXIII was the active agent in plasma FXIII concentrates and to better understand the potential therapeutic use of this protein. Colitis was induced by instillation of 12% 2,4,6-trinitrobenzenesulfonic acid (TNBS) in 50% ethanol into the colon of male Wistar rats. Rats were treated with 0.65 mg/kg rFXIII or vehicle (intravenously) daily for 10 days. Treatment was started either immediately after TNBS/EtOH instillation (to evaluate effects on developing lesions) or seven days later (to evaluate effects on established lesions). In both cases rats were killed either immediately after the end of treatment (to evaluate immediate effects) or 17 days later (to evaluate long-lasting effects). The effects of rFXIII were compared to positive (5-amino-2-hydroxybenzoic acid) control over a 35-day time course. The severity of lesions was determined by colon weight and macroscopic and histologic scores. Transglutaminase activity was measured in both colon tissue and serum. rFXIII treatment reduced lesion severity significantly not only in developing but also in established lesions. Improvements in healing persisted at least 18 days after treatment was discontinued. Serum and tissue transglutaminase levels were restored by rFXIII treatment. In conclusion, pure rFXIII is as effective as plasma FXIII concentrates in a rat model of experimental colitis. In addition, rFXIII significantly improves the healing of preexisting lesions, a characteristic useful in treatment of human inflammatory bowel diseases.

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REFERENCES

  1. D'Argenio G, Ciacci C, Sorrentini I, Iovino P, Gatto A, Cosenza V, Mazzacca G: Serum transglutaminase in inflammatory bowel diseases. J Clin Gastroenterol 12:400-404, 1990

    Google Scholar 

  2. Seitz R, Leugner F, Katschinski M, Immel A, Kraus M, Egbring R, Goke B: Ulcerative colitis and Crohn's disease: Factor XIII, inflammation and haemostasis. Digestion 55:361-367, 1994

    Google Scholar 

  3. Stadnicki A, Kloczko J, Nowak A, Sierka E: Alterations of haemostasis parameters with special reference to factor XIII and fibronectin in patients with ulcerative colitis. Eur J Gastroenterol Hepatol 4:743-746, 1992

    Google Scholar 

  4. Lorenz R, Olbert P, Born P: Factor XIII in chronic inflammatory bowel diseases. Semin Thromb Hemost 22:451-455, 1996

    Google Scholar 

  5. Lorenz R, Heinmuller M, Classen M, Tornieporth N, Gain T: Substitution of factor XIII: A therapeutic approach to ulcerative colitis. Haemostasis 21:5-9, 1991

    Google Scholar 

  6. Lorenz R, Born P, Classen M: Substitution of factor XIII concentrate in treatment refractory ulcerative colitis. A prospective pilot study. Med Klin 89:534-537, 1994 (in German)

    Google Scholar 

  7. Oshitani N, Nakamura S, Matsumoto T, Kobayashi K, Kitano A: Treatment of Crohn's disease fistulas with coagulation factor XIII. Lancet 347:119-120, 1996 (letter)

    Google Scholar 

  8. Takamatsu H, Akiyama H, Ibara S, Seki S, Kuraya K, Ikenoue T: Treatment for necrotizing enterocolitis perforation in the extremely premature infant (weighing less than 1,000 g). J Pediatr Surg 27:741-743, 1992

    Google Scholar 

  9. Aeschlimann D, Paulsson M: Transglutaminases: Protein cross-linking enzymes in tissues and body fluids. Thromb Haemost 71:402-415, 1994

    Google Scholar 

  10. McDonagh J, Hidetake F: Determinants of substrate specificity for factor XIII. Semin Thromb Hemost 22:369-176, 1996

    Google Scholar 

  11. Lorand L, Losowsky MS, Miloszewski KJ: Human factor XIII: Fibrin-stabilizing factor. Prog Hemost Thromb 5:245-290, 1980

    Google Scholar 

  12. Loewy AG, Dvilansky A, Britten AF, Matacic S, Darnell JH: Some thoughts on the state in nature, biosynthetic origin, and function of factor XIII. Ann NY Acad Sci 202:41-58, 1972

    Google Scholar 

  13. Aeshlimann D, Mosher D, Paulsson M. Tissue transglutaminase and factor XIII in cartilage and bone remodeling. Semin Thromb Hemost 22:437-444, 1996

    Google Scholar 

  14. McDonagh J: Structure and function of factor XIII. In Hemostasis and Thrombosis, Basic Principles and Practice, 3rd ed. R Colman, J Hirsh, V Marder, E Salzman (eds). Philadelphia, JB Lippincott, 1993, pp 301-313

    Google Scholar 

  15. Devine DV, Bishop PD: Platelet-associated factor XIII in platelet activation, adhesion and clot stabilization. Semin Thromb Hemost 22:409-413, 1996

    Google Scholar 

  16. Adany R: Intracellular factor XIII: Cellular distribution of factor XIII subunit a in humans. Semin Thromb Hemost 22:399-408, 1996

    Google Scholar 

  17. Henriksson P, Becker S, Lynch G, McDonagh J: Identification of intracellular factor XIII in human monocytes and macrophages. J Clin Invest 76:528-534, 1985

    Google Scholar 

  18. Muszbek L, Adany R, Szegedi G, Polgar J, Kavai M: Factor XIII of blood coagulation in human monocytes. Thromb Res 37:401-410, 1985

    Google Scholar 

  19. Muszbek L, Polgar J, Fesus L: Kinetic determination of blood coagulation factor XIII in plasma. Clin Chem 31:35-40, 1985

    Google Scholar 

  20. Schwartz ML, Pizzo SV, Hill RL, McKee PA, Fisher S, Schwartz M, Gottlieb A, Yoseph NB, Shapiro S. The subunit structures of human plasma and platelet factor XIII. J Biol Chem 246:5851-5854, 1971

    Google Scholar 

  21. Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL: Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 96:795-803, 1989

    Google Scholar 

  22. Banerjee AK, Peters TJ: Experimental non-steroidal antiinflammatory drug-induced enteropathy in the rat: similarities to inflammatory bowel disease and effect of thromboxane synthetase inhibitors. Gut 31:1358-1364, 1990

    Google Scholar 

  23. Eliakim R, Karmeli F, Okon E, Rachmilewitz D: Ketotifen effectively prevents mucosal damage in experimental colitis. Gut 33:1498-1503, 1992

    Google Scholar 

  24. D'Argenio G, Cosenza V, Sorrentini I, De Ritis F, Gatto A, Delle Cave M, D'Armiento FP, Mazzacca G: Butyrate, mesalamine, and factor XIII in experimental colitis in the rat: Effects on transglutaminase activity. Gastroenterology 106:399-404, 1994

    Google Scholar 

  25. Wallace JL, MacNaughton WK, Morris GP, Beck PL: Inhibition of leukotriene synthesis markedly accelerates healing in a rat model of inflammatory bowel disease. Gastroenterology 96:29-36, 1989

    Google Scholar 

  26. Wallace JL, Keenan CM: An orally active inhibitor of leukotriene synthesis accelerates healing in a rat model of colitis. Am J Physiol 258:G527-G534, 1990

    Google Scholar 

  27. Bishop PD, Teller DC, Smith RA, Lasser GW, Gilbert T, Seale RL: Expression, purification, and characterization of human factor XIII in Saccharomyces cerevisiae. Biochemistry 29:1861-1869, 1990

    Google Scholar 

  28. Hornyak TJ, Bishop PD, Shafer JA: Alpha-thrombin-catalyzed activation of human platelet factor XIII: Relationship between proteolysis and factor XIIIa activity. Biochemistry 28:7326-7332, 1989

    Google Scholar 

  29. Yee VC, Pedersen LC, Le Trong I, Bishop PD, Stenkamp RE, Teller DC: Three-dimensional structure of a transglutaminase: Human blood coagulation factor XIII. Proc Natl Acad Sci USA 91:7296-7300, 1994

    Google Scholar 

  30. Bishop PD, Lasser GW, Le Trong I, Stenkamp RE, Teller DC: Human recombinant factor XIII from Saccharomyces cerevisiae. Crystallization and preliminary x-ray data. J Biol Chem 265:13888-13889, 1990

    Google Scholar 

  31. Lorand L, Campbell-Wilkes LK, Cooperstein L: A filter paper assay for transamidating enzymes using radioactive amine substrates. Anal Biochem 50:623-631, 1972

    Google Scholar 

  32. D'Argenio G, Sorrentini I, Cosenza V, Gatto A, Iovino P, D'Armiento FP, Baldassarre F, Mazzacca G: Serum and tissue transglutaminase correlates with the severity of inflammation in induced colitis in the rat. Scand J Gastroenterol 27:111-114, 1992

    Google Scholar 

  33. D'Argenio G, Biancone L, Cosenza V, Della Valle N, D'Armiento FP, Boirivant M, Pallone F, Mazzacca G: Transglutaminases in Crohn's disease. Gut 37:690-695, 1995

    Google Scholar 

  34. Lorenz R, Born P, Olbert P, Classen M: Factor XIII substitution in ulcerative colitis. Lancet 345:449-450, 1995

    Google Scholar 

  35. Kuis W, Malchow H, Behnke MKE, Emmrich J, Hamling J, Lorenz R: Additive factor XIII treatment for severe ulcerative colitis. A double blind placebo-controlled trial. Gastroenterology 114:G4152, 1998 (abstract)

    Google Scholar 

  36. Stief TW: Factor XIII of blood coagulation inhibits the oxidative phagocyte metabolism and suppresses the immune response in vivo. Thromb Res 63:227-238, 1991

    Google Scholar 

  37. Hirahara K, Shinbo K, Takahashi M, Matsuishi T: Suppressive effect of human blood coagulation factor XIII on the vascular permeability induced by anti-guinea pig endothelial cell antiserum in guinea pigs. Thromb Res 71:139-148, 1993

    Google Scholar 

  38. Benfer J, Struck H: Factor XIII and fracture healing. An experimental study. Eur Surg Res 9:217-223, 1977

    Google Scholar 

  39. Board PG, Losowsky MS, Miloszewski KJ: Factor XIII: inherited and acquired deficiency. Blood Rev 7:229-242, 1993

    Google Scholar 

  40. Bowness JM, Henteleff H, Dolynchuk KN: Components of increased labelling with putrescine and fucose during healing of skin wounds. Connect Tissue Res 16:57-70, 1987

    Google Scholar 

  41. Duckert F, Nyman D: Factor XIII, fibrin and collagen. Suppl Thromb Haemost 63:391-396, 1978

    Google Scholar 

  42. Powanda MC, Moyer ED: Plasma proteins and wound healing. Surg Gynecol Obstet 153:749-755, 1981

    Google Scholar 

  43. Wang JY, Johnson LR: Role of transglutaminase and protein cross-linking in the repair of mucosal stress erosions. Am J Physiol 262:G818-G825, 1992

    Google Scholar 

  44. Loguercio C, D'Argenio G, Delle Cave M, Cosenza V, Della Valle N, Mazzacca G, Del Vecchio Blanco C: Direct evidence of oxidative damage in acute and chronic phases of experimental colitis in rats. Dig Dis Sci 41(6):1204-1211, 1996

    Google Scholar 

  45. Antalis TM, Reeder JA: Butyrate regulates gene expression of the plasminogen activating system in colon cancer cells. Int J Cancer 62:619-626, 1995

    Google Scholar 

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Authors and Affiliations

  1. Gastrointestinal Unit, School of Medicine, Federico II University, Naples, Italy

    Giuseppe D'argenio, Angelika Grossman, Vittorio Cosenza, Nicola Della Valle, Gabriele Mazzacca & Paul D. Bishop

  2. ZymoGenetics, Inc., Seattle, Washington

    Giuseppe D'argenio, Angelika Grossman, Vittorio Cosenza, Nicola Della Valle, Gabriele Mazzacca & Paul D. Bishop

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  1. Giuseppe D'argenio
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  2. Angelika Grossman
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  3. Vittorio Cosenza
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  4. Nicola Della Valle
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  5. Gabriele Mazzacca
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  6. Paul D. Bishop
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D'argenio, G., Grossman, A., Cosenza, V. et al. Recombinant Factor XIII Improves Established Experimental Colitis in Rats. Dig Dis Sci 45, 987–997 (2000). https://doi.org/10.1023/A:1005541512152

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