| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
The incidence of allergic diseases including bronchial asthma is worldwide consistently increasing, the incidence being particularly remarkable in the Japanese population. Despite the availability of a number of drugs, such as inhaled steroids, for the treatment of bronchial asthma, there are still many patients with intractable disease as well as a high rate of mortality. Thus, there is an urgent need to develop novel therapies to improve the prognosis and quality of life of allergic patients. To date we have focused our investigation on the role of the coagulation and fibrinolysis pathways in the pathogenesis of inflammatory diseases of the lung including bronchial asthma. In addition, we have reported that the effector enzyme of the anticoagulant pathway, activated protein C(APC) has anti-inflammatory properties, and demonstrated that it is effective for the treatment of bronchial asthma in mouse experimental models. To clarify the mechanism by which APC is capable of exerting anti-
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inflammatory and anti-allergic effects, in the current investigation, we evaluated the inhibitory effect of APC on dendritic cell-mediated activation of lymphocytes, secretion of cytokines from Th2 cells and IgE release from B lymphocytes. We also investigated the intracellular pathways involved in APC-mediated action. During the current investigational project, we demonstrated that, in the ovalbumin-induced bronchial asthma experimental model, APC inhibits dendritic cell-mediated activation of lymphocytes, secretion of IL-4,IL-5,IL-13 from T cells and IgE from B cells. We also demonstrated that APC exerts its anti-allergic action by inhibiting the activation of the protein kinase C pathway and the nuclear translocation of the STAT6 and NFκB transcription factors. In conclusion, this study demonstrated that the effectiveness of APC to inhibit the immune response and suggest its potential usefulness as a novel therapeutic drug for allergic diseases, particularly for the treatment of bronchial asthma. Less
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