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Role of Thrombin-Activatable Fibrinolysis Inhibitor in Allergic Bronchial Asthma

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Abstract

Background

Bronchial asthma is an inflammatory disease of the airways. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase that besides inhibiting fibrinolysis, also regulates inflammatory processes. The only validated substrate known for TAFI is fibrin. In the present study we evaluated the role of TAFI in bronchial asthma by comparing the development of allergic bronchial asthma between wild-type (WT) and TAFI-deficient mice (KO).

Methods

Asthmatic inflammation was induced by sensitization and challenge with ovalbumin in WT (WT/OVA) and TAFI KO (KO/OVA) mice. WT mice (WT/SAL) and TAFI KO (KO/SAL) were used as controls. Cytokines, markers of inflammation, and coagulation were measured in bronchoalveolar lavage fluid (BALF).

Results

Airway hyperresponsiveness was worse in KO/OVA mice than in WT/OVA mice or control mice. Markers of lung injury were significantly increased in BALF from KO/OVA mice compared to WT/OVA mice. Airway hyperresponsiveness and the BALF concentrations of IL-5 and osteopontin were significantly increased in KO/OVA mice compared to WT/OVA mice. Treatment of WT/OVA and KO/OVA mice with a C5a receptor antagonist significantly decreased hyperresponsiveness along with the BALF concentrations of total protein and C5a compared to untreated asthmatic mice.

Conclusion

The results of this study suggest that TAFI plays a protective role in the pathogenesis of allergic inflammation probably by inhibiting the complement system.

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References

  1. Subbarao P, Mandhane PJ, Sears MR (2009) Asthma: epidemiology, etiology and risk factors. CMAJ 181:E181–E190

    Article  PubMed  Google Scholar 

  2. Robinson DS (2010) The role of the T cell in asthma. J Allergy Clin Immunol 126:1081–1091

    Article  PubMed  CAS  Google Scholar 

  3. Bouma BN, Meijers JC (2003) Thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B, procarboxypeptidase R, procarboxypeptidase U). J Thromb Haemost 1:1566–1574

    Article  PubMed  CAS  Google Scholar 

  4. Morser J, Gabazza EC, Myles T, Leung LL (2010) What has been learnt from the thrombin-activatable fibrinolysis inhibitor-deficient mouse? J Thromb Haemost 8:868–876

    PubMed  CAS  Google Scholar 

  5. Mosnier LO, Bouma BN (2006) Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol 26:2445–2453

    Article  PubMed  CAS  Google Scholar 

  6. Bajzar L, Jain N, Wang P, Walker JB (2004) Thrombin activatable fibrinolysis inhibitor: not just an inhibitor of fibrinolysis. Crit Care Med 32:S320–S324

    Article  PubMed  CAS  Google Scholar 

  7. Krug N, Tschernig T, Erpenbeck VJ, Hohlfeld JM, Kohl J (2001) Complement factors C3a and C5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma. Am J Respir Crit Care Med 164:1841–1843

    PubMed  CAS  Google Scholar 

  8. Karp CL, Grupe A, Schadt E, Ewart SL, Keane-Moore M, Cuomo PJ, Kohl J, Wahl L, Kuperman D, Germer S, Aud D, Peltz G, Wills-Karp M (2000) Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 1:221–226

    Article  PubMed  CAS  Google Scholar 

  9. Walters DM, Breysse PN, Schofield B, Wills-Karp M (2002) Complement factor 3 mediates particulate matter-induced airway hyperresponsiveness. Am J Respir Cell Mol Biol 27:413–418

    PubMed  CAS  Google Scholar 

  10. Humbles AA, Lu B, Nilsson CA, Lilly C, Israel E, Fujiwara Y, Gerard NP, Gerard C (2000) A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 406:998–1001

    Article  PubMed  CAS  Google Scholar 

  11. Drouin SM, Corry DB, Hollman TJ, Kildsgaard J, Wetsel RA (2002) Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy. J Immunol 169:5926–5933

    PubMed  CAS  Google Scholar 

  12. Bautsch W, Hoymann HG, Zhang Q, Meier-Wiedenbach I, Raschke U, Ames RS, Sohns B, Flemme N, Vilsendorf AMZ, Grove M, Klos A, Kohl J (2000) Cutting edge: guinea pigs with a natural C3a-receptor defect exhibit decreased bronchoconstriction in allergic airway disease: evidence for an involvement of the C3a anaphylatoxin in the pathogenesis of asthma. J Immunol 165:5401–5405

    PubMed  CAS  Google Scholar 

  13. Taube C, Rha YH, Takeda K, Park JW, Joetham A, Balhorn A, Dakhama A, Giclas PC, Holers VM, Gelfand EW (2003) Inhibition of complement activation decreases airway inflammation and hyperresponsiveness. Am J Respir Crit Care Med 168:1333–1341

    Article  PubMed  Google Scholar 

  14. Paczkowski NJ, Finch AM, Whitmore JB, Short AJ, Wong AK, Monk PN, Cain SA, Fairlie DP, Taylor SM (1999) Pharmacological characterization of antagonists of the C5a receptor. Br J Pharmacol 128:1461–1466

    Article  PubMed  CAS  Google Scholar 

  15. Finch AM, Wong AK, Paczkowski NJ, Wadi SK, Craik DJ, Fairlie DP, Taylor SM (1999) Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a. J Med Chem 42:1965–1974

    Article  PubMed  CAS  Google Scholar 

  16. Nagashima M, Yin ZF, Zhao L, White K, Zhu Y, Lasky N, Halks-Miller M, Broze GJ Jr, Fay WP, Morser J (2002) Thrombin-activatable fibrinolysis inhibitor (TAFI) deficiency is compatible with murine life. J Clin Invest 109:101–110

    PubMed  CAS  Google Scholar 

  17. Yuda H, Adachi Y, Taguchi O, Gabazza EC, Hataji O, Fujimoto H, Tamaki S, Nishikubo K, Fukudome K, D’Alessandro-Gabazza CN, Maruyama J, Izumizaki M, Iwase M, Homma I, Inoue R, Kamada H, Hayashi T, Kasper M, Lambrecht BN, Barnes PJ, Suzuki K (2004) Activated protein C inhibits bronchial hyperresponsiveness and Th2 cytokine expression in mice. Blood 103:2196–2204

    Article  PubMed  CAS  Google Scholar 

  18. Murphy DM, O’Byrne PM (2010) Recent advances in the pathophysiology of asthma. Chest 137:1417–1426

    Article  PubMed  CAS  Google Scholar 

  19. Ma Z, Paek D, Oh CK (2009) Plasminogen activator inhibitor-1 and asthma: role in the pathogenesis and molecular regulation. Clin Exp Allergy 39:1136–1144

    Article  PubMed  CAS  Google Scholar 

  20. Samitas K, Zervas E, Vittorakis S, Semitekolou M, Alissafi T, Bossios A, Gogos H, Economidou E, Lotvall J, Xanthou G, Panoutsakopoulou V, Gaga M (2011) Osteopontin expression and relation to disease severity in human asthma. Eur Respir J 37:331–341

    Article  PubMed  CAS  Google Scholar 

  21. Halwani R, Al-Muhsen S, Al-Jahdali H, Hamid Q (2011) Role of transforming growth factor-beta in airway remodeling in asthma. Am J Respir Cell Mol Biol 44:127–133

    Article  PubMed  CAS  Google Scholar 

  22. Ali H (2010) Regulation of human mast cell and basophil function by anaphylatoxins C3a and C5a. Immunol Lett 128:36–45

    Article  PubMed  CAS  Google Scholar 

  23. Thorburn AN, Hansbro PM (2010) Harnessing regulatory T cells to suppress asthma: from potential to therapy. Am J Respir Cell Mol Biol 43:511–519

    Article  PubMed  CAS  Google Scholar 

  24. Matthay MA, Clements JA (2004) Coagulation-dependent mechanisms and asthma. J Clin Invest 114:20–23

    PubMed  CAS  Google Scholar 

  25. Gabazza EC, Taguchi O, Tamaki S, Takeya H, Kobayashi H, Yasui H, Kobayashi T, Hataji O, Urano H, Zhou H, Suzuki K, Adachi Y (1999) Thrombin in the airways of asthmatic patients. Lung 177:253–262

    Article  PubMed  CAS  Google Scholar 

  26. Shinagawa K, Martin JA, Ploplis VA, Castellino FJ (2007) Coagulation factor Xa modulates airway remodeling in a murine model of asthma. Am J Respir Crit Care Med 175:136–143

    Article  PubMed  CAS  Google Scholar 

  27. Shimizu S, Shimizu T, Morser J, Kobayashi T, Yamaguchi A, Qin L, Toda M, D’Alessandro-Gabazza C, Maruyama T, Takagi T, Yano Y, Sumida Y, Hayashi T, Takei Y, Taguchi O, Suzuki K, Gabazza EC (2008) Role of the coagulation system in allergic inflammation in the upper airways. Clin Immunol 129:365–371

    Article  PubMed  CAS  Google Scholar 

  28. Cho SH, Ryu CH, Oh CK (2004) Plasminogen activator inhibitor-1 in the pathogenesis of asthma. Exp Biol Med (Maywood) 229:138–146

    CAS  Google Scholar 

  29. Schneider DJ, Chen Y, Sobel BE (2008) The effect of plasminogen activator inhibitor type 1 on apoptosis. Thromb Haemost 100:1037–1040

    PubMed  CAS  Google Scholar 

  30. Balsara RD, Ploplis VA (2008) Plasminogen activator inhibitor-1: the double-edged sword in apoptosis. Thromb Haemost 100:1029–1036

    PubMed  CAS  Google Scholar 

  31. Nemeth K, Keane-Myers A, Brown JM, Metcalfe DD, Gorham JD, Bundoc VG, Hodges MG, Jelinek I, Madala S, Karpati S, Mezey E (2010) Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma. Proc Natl Acad Sci USA 107:5652–5657

    Article  PubMed  CAS  Google Scholar 

  32. Alcorn JF, Rinaldi LM, Jaffe EF, van Loon M, Bates JH, Janssen-Heininger YM, Irvin CG (2007) Transforming growth factor-beta 1 suppresses airway hyperresponsiveness in allergic airway disease. Am J Respir Crit Care Med 176:974–982

    Article  PubMed  CAS  Google Scholar 

  33. Wills-Karp M (2007) Complement activation pathways: a bridge between innate and adaptive immune responses in asthma. Proc Am Thorac Soc 4:247–251

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

The present investigation was supported by Grants-in-Aid (Nos. 18590846 and 17590788) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. JM was supported by JSPS scholarship L8020.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Pulmonary and Critical Care Medicine, Mie University School of Medicine, Edobashi 2-174, Tsu City, Mie Prefecture, 514-8507, Japan

    Atsushi Fujiwara, Osamu Taguchi, Takehiro Takagi, Corina N. D’Alessandro-Gabazza, Hiroyasu Kobayashi, Tetsu Kobayashi & Masahiro Naito

  2. Department of Immunology, Mie University School of Medicine, Edobashi 2-174, Tsu City, Mie Prefecture, 514-8507, Japan

    Corina N. D’Alessandro-Gabazza, Daniel Boveda-Ruiz, Masaaki Toda, Atsushi Yasukawa, Yuki Matsushima, Yasushi Miyake & Esteban C. Gabazza

  3. Mie Prefecture General Hospital, 5450-132, Hinaga, Yokkaichi, Mie, 510-0885, Japan

    Masamichi Yoshida

  4. Division of Hematology, Stanford University School of Medicine, Stanford, CA, 94305, USA

    John Morser

  5. Department of Gastroenterology and Hepatology, Mie University School of Medicine, Edobashi 2-174, Tsu City, Mie Prefecture, 514-8507, Japan

    Paloma Gil-Bernabe & Yoshiyuki Takei

Authors
  1. Atsushi Fujiwara
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  2. Osamu Taguchi
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  3. Takehiro Takagi
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  17. Esteban C. Gabazza
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Corresponding author

Correspondence to Esteban C. Gabazza.

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Fujiwara, A., Taguchi, O., Takagi, T. et al. Role of Thrombin-Activatable Fibrinolysis Inhibitor in Allergic Bronchial Asthma. Lung 190, 189–198 (2012). https://doi.org/10.1007/s00408-011-9337-9

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  • DOI: https://doi.org/10.1007/s00408-011-9337-9

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