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Protection of Plasminogen Activator Inhibitor-1-Deficient Mice from Nasal Allergy¹

Takayuki Sejima^*,, Seiji Madoiwa, Jun Mimuro, Teruko Sugo, Kiyotaka Okada, Shigeru Ueshima, Osamu Matsuo, Takashi Ishida, Keiichi Ichimura^* and Yoichi Sakata^2,

^* Department of Otorhinolaryngology-Head and Neck Surgery, and Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical School, and Department of Otorhinolaryngology, International University of Health and Welfare Hospital, Tochigi, Japan; and Department of Physiology II, Kinki University School of Medicine, Osakasayama City, Osaka, Japan

This study was performed to clarify the relationship between fibrinolytic components and the pathology of allergy, particularly that during the development of nasal allergy and nasal tissue changes. Intranasal OVA challenge after sensitization by i.p. administration of OVA induced a higher level of excess subepithelial collagen deposition in wild-type (WT) C57BL/6J mice than in plasminogen activator inhibitor (PAI)-1-deficient (PAI-1^–/–) mice. The excess PAI-1 induction in the nasal mucosa and higher level of active PAI-1 in the nasal lavage fluid of WT-OVA mice compared with those in WT-control mice suggested that the decrease of proteolytic activity inhibits the removal of subepithelial collagen. The frequency of sneezing, nasal rubbing, nasal hyperresponsiveness, production of specific IgG1 and IgE in the serum, and production of 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 IFN- in splenocyte culture medium increased significantly. Histopathologically, there were 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 immune response.

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