| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥270,000)
Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Aim : Accompanying induction of anti-rheumatic drug such as leflunomide, molecular targeting drug such as TKIs, fatal acute lung injury has been frequently reported in Japanese patients. On the other hands, acute exacerbation of idiopathic interstitial pneumonia, particularly of idiopathic pulmonary fibrosis have been known fatal phenomenon in Japanese, recently been realized more frequent in Japanese than people in outside of Japan. In this research, we focused on surfactant protein production and epithelial mesenchymal transition (EMT) in vitro and in vivo, modulated by HMR1726, active form of leflunomide.
Methods : Using H441 cell line producing SP-B, and A549 epithelium cell line, we investigated expression of mRNA of SP-b and EMT, under the condition of presence or absence of HMR1726, predonisolone (PSL), TNF-alpha and/or TGF-beta. We also investigated affects of leflunomide and PSL on SP-B production in C57BL/6 mice lung.
Results : Under the existence of TNF-alpha and/or TGF-beta, PSL and HMR1726 inhibited SP-B mRNA expression and protein production. But, HMR1726 alone or HMR1726 and PSL did not inhibit SP-B mRNA expression under absence of TNF-alpha and TGF-beta. Alpha smooth muscle actin (SMA) production in A549 cell was enhanced by HMR1726. In vivo study, SP-B expression was induced by PSL 60 or 90mg/kg inoculation for two days in C57BL/6 mice.
Summary : PSL enhanced SP-B production in vitro and in vivo. SP-B synthesis was not affected by HMR1726 alone treatment, but inhibited by presence of TNF-alpha and TGF-beta. Furthermore, HMR1726 and TNF-alpha + TGF-beta induced alpha-SMA production, EMT like phenomenon. These results suggest drug-induced lung injury might lead EMT subsequently pulmonary fibrosis, so treatment of drug-induced lung injury needs to focus on 'inhibition of transforming process of EMT'.
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