Role of Fibrinolysis in the Nasal System

  • Takayuki Sejima
  • Yoichi Sakata


In this chapter, we show the presence of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), and plasminogen activator inhibitor-1 (PAI-1) in nasal mucosa. It is suggested that t-PA synthesized in mucous cells is promptly secreted and modifies the watery nasal discharge in allergic rhinitis and that u-PA activity may help with the passage of large amounts of rhinorrhea by reducing its viscosity. Furthermore, we clarify the relation between fibrinolytic components and the pathology of allergy, particularly during the development of nasal allergy and nasal tissue changes. Wild-type (WT) mice can develop nasal allergy for ovalbumin (OVA) sensitization, but PAI-1-deficient mice (PAI-1-/-) cannot. The production of specific immunoglobulins IgG1 and IgE in the serum and production of interleukins IL-4 and IL-5 in splenocyte culture supernatant increased significantly in WT-OVA mice. In PAI-1-/- mice, these reactions were absent, and specific IgG2a in serum and interferon-γ in splenocyte culture medium increased significantly. Histopathologically, there was marked goblet cell hyperplasia and eosinophil infiltration into the nasal mucosa in WT-OVA mice, but these were absent in PAI-1-/- mice. These results indicate that the immune response in WT-OVA mice can be classified as a dominant Th2 response, which would promote collagen deposition. In contrast, the Th2 response in PAI-1-/- mice was down-regulated and the immune response shifted from Th2-dominant reaction to a Th1-dominant one. Taken together, these findings suggest that PAI-1 plays an important role not only in thrombolysis but also in the immune response.

Key words

PAI-1 t-PA u-PA Nasal allergy Transgenic/knockout mice 


  1. 1.
    Liu YX, Peng XR, Ny T (1991) Tissue-specific and time-coordinated hormone regulation of plasminogen-activator-inhibitor type 1 and tissue-type plasminogen activator in the rat ovary during gonadotropin-induced ovulation. Eur J Biochem 195:549–555PubMedCrossRefGoogle Scholar
  2. 2.
    Schneiderman J, Bordin GM, Engelberg I, et al (1995) Expression of fibrinolytic genes in atherosclerotic abdominal aortic aneurysm wall. J Clin Invest 96:639–645PubMedCrossRefGoogle Scholar
  3. 3.
    Bugge TH, Kombrinck KW, Flick MJ, et al (1996) Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 87:709–719PubMedCrossRefGoogle Scholar
  4. 4.
    Carmeliet P, Moons L, Pioplis V, et al (1997) Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J Clin Invest 99:200–208PubMedCrossRefGoogle Scholar
  5. 5.
    Oh CK, Ariue B, Alban RF, et al (2002) PAI-1 promotes extracellular matrix deposition in the airways of a murine asthma model. Biochem Biophys Res Commun 294: 1155–1160PubMedCrossRefGoogle Scholar
  6. 6.
    Gyetko MR, Sud S, Chen GH, et al (2002) Urokinase-type plasminogen activator is required for the generation of a type 1 immune response to pulmonary Cryptococcus neoformans infection. J Immunol 168:801–809PubMedGoogle Scholar
  7. 7.
    Gyetko MR, Sud S, Chensue SW (2004) Urokinase-deficient mice fail to generate a type 2 immune response following schistosomal antigen challenge. Infect Immun 72:461–467PubMedCrossRefGoogle Scholar
  8. 8.
    Sejima T, Madoiwa S, Mimuro J, et al (2004) Expression profiles of fibrinolytic components in nasal mucosa. Histochem Cell Biol 122:61–73PubMedCrossRefGoogle Scholar
  9. 9.
    Larsen K, Maat MPM, Jespersen J (1997) Plasminogen activators in human nasal polyps and mucosa. Rhinology 35:175–177PubMedGoogle Scholar
  10. 10.
    Åkerlund A, Greiff L, Andersson M, et al (1993) Mucosal exudation of fibrinogen in coronavirus-induced common colds. Acta Otolaryngol 113:642–648PubMedCrossRefGoogle Scholar
  11. 11.
    Sadwey M, Loskutoff DJ (1991) Regulation murine plasminogen activator inhibitor 1 gene expression in vivo: tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-α, and transforming growth factor-β. J Clin Invest 88:1346–1353CrossRefGoogle Scholar
  12. 12.
    Jensen PJ, Rodeck U (1993) Autocrine/paracrine regulation of keratinocyte urokinase plasminogen activator through the TGF-α/EGF receptor. J Cell Physiol 155:133–139CrossRefGoogle Scholar
  13. 13.
    Holgate ST (1998) Airway remodeling. Eur Respir Rev 8:1007–1011Google Scholar
  14. 14.
    Bousquet J, Jeffery PK, Busse WB, et al (2000) Asthma: from bronchoconstriction to airway remodeling. Am J Respir Crit Care Med 61:1720–1745Google Scholar
  15. 15.
    Collen D (1999) The plasminogen (fibrinolytic) system. Thromb Haemost 82:259–270PubMedGoogle Scholar
  16. 16.
    Sanai A, Nagata H, Konno A (1999) Extensive interstitial collagen deposition on the basement membrane zone in allergic nasal mucosa. Acta Otolaryngol 119:473–478PubMedCrossRefGoogle Scholar
  17. 17.
    Boulet L, Laviolette M, Turcotte H, et al (1997) Bronchial subepithelial fibrosis correlates with airway responsiveness to methacholine. Chest 112:45–52PubMedCrossRefGoogle Scholar
  18. 18.
    Sejima T, Madoiwa S, Mimuro J, et al (2005) Protection of plasminogen activator inhibitor-1 deficient mice from nasal allergy. J Immunol 174:8135–8143PubMedGoogle Scholar
  19. 19.
    Hattori N, Degen JL, Sisson TH, et al (2000) Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice. J Clin Invest 106:1341–1350PubMedCrossRefGoogle Scholar
  20. 20.
    Mosmann TR, Cherwinski H, Bond MW, et al (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357PubMedGoogle Scholar
  21. 21.
    Sandler NG, Mentink-Kane MM, Cheever AW, et al (2003) Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J Immunol 171:3655–3667PubMedGoogle Scholar
  22. 22.
    Del Prete G, Maggi E, Parronch P, et al (1988) IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. J Immunol 140:4193–4198PubMedGoogle Scholar
  23. 23.
    Ueda A, Chandswang N, Ovary Z (1990) The action of interleukin-4 on antigen-specific IgG1 and IgE production by interaction in vivo primed B cells and carrier-specific cloned Th2 cells. Cell Immunol 128:31–34PubMedCrossRefGoogle Scholar
  24. 24.
    Lopez AF, Sanderson CJ, Gamble JR, et al (1988) Recombinant human interleukin 5 is a selective activator of human eosinophil function. J Exp Med 167:219–224PubMedCrossRefGoogle Scholar
  25. 25.
    Yamaguchi Y, Hayashi Y, Sugama Y, et al (1988) Highly purified murine interleukin 5 (IL-5) stimulates eosinophil function and prolongs in vitro survival: IL-5 as an eosinophil chemotactic factor. J Exp Med 167:1737–1742PubMedCrossRefGoogle Scholar
  26. 26.
    Deng G, Curriden SA, Hu G, et al (2001) Plasminogen activator inhibitor-1 regulates cell adhesion by binding to the somatomedin B domain of vitronectin. J Cell Physiol 189:23–33PubMedCrossRefGoogle Scholar
  27. 27.
    Tarui T, Andronicos N, Czekay RP, et al (2003) Critical role of integrin α5β1 in urokinase (uPA)/urokinase receptor (uPAR, CD87) signaling. J Biol Chem 278:29863–29872PubMedCrossRefGoogle Scholar
  28. 28.
    Dano K, Andreasen PA, Grondahl-Hansen J, et al (1985) Plasminogen activators, tissue degradation and cancer. Adv Cancer Res 44:139–266PubMedCrossRefGoogle Scholar
  29. 29.
    Cho SH, Hall IP, Wheatley M, et al (2001) Possible role of the 4G/5G polymorphism of the plasminogen activator inhibitor 1 gene in the development of asthma. J Allergy Clin Immunol 108:212–214PubMedCrossRefGoogle Scholar
  30. 30.
    Bucková D, Izakovicova Hollá L, Vácha J (2002) Polymorphism 4G/5G in the plasminogen activator inhibitor-1 (PAI-1) gene is associated with IgE-mediated allergic diseases and asthma in the Czech population. Allergy 57:446–448PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Takayuki Sejima
    • 1
  • Yoichi Sakata
    • 2
  1. 1.Department of Otolaryngology-Head & Neck SurgeryJichi Medical UniversityShimotsuke, TochigiJapan
  2. 2.Division of Cell and Molecular Medicine, Center for Molecular MedicineJichi Medical UniversityShimotsuke, TochigiJapan

Personalised recommendations