Induction of pulmonary fibrosis by methotrexate treatment in mice lung in vivo and in vitro
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概要
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Methotrexate (MTX) has been used as the first-line disease-modifying antirheumatic drug (DMARD) in patients with early progressive rheumatoid arthritis (RA). Several severe side effects such as myelosuppression, hepato-, nephro-, and pulmonary toxicities have been reported. However, the pathogenic mechanism of MTX-induced pulmonary fibrosis is still unknown. Here, we evaluated the morphological and biological changes of the pulmonary fibrosis in mice treated with MTX. Three, four and five weeks after consecutive administration of MTX (3 mg/kg/day), hydroxyproline content in the lung tissues increased significantly to about 2 times higher that of the control level. This result closely reflected to the results of hematoxylin and eosin (HE) and Azan stains. Immunohistochemical analysis revealed that MTX treatment resulted in a decrease of alveolar epithelial cells and an increase of fibroblast cells in the mouse lung tissues. When we examined the effects of MTX on primary mouse alveolar epithelial cell (MAEC) and mouse lung fibroblast (MLF) survival in vitro, the efficiency of MTX-induced cytotoxicity and apoptosis in MAEC was more sensitive than MLF cells. Thus, our results indicate that the administration of MTX by an oral route could induce a fibrotic response with cell dysfunction of the alveolar epithelium by which MTX-induced apoptosis. Our results thus suggest that MTX could induce alveolar epithelial cell injury and resulted in the loss of integrity of the alveolar-capillary barrier basement membranes followed by the recruitment and proliferation of myofibroblasts with the deposition of collagens.
- 2010-10-01
著者
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Yamamoto Toshinori
Drug Safety Research & Development Pfizer Global Research & Development Nagoya Laboratories
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Yamamoto T
Showa Univ. Tokyo Jpn
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Yamamoto Toshinori
Department Of Biochemical Toxicology School Of Pharmaceutical Sciences Showa University
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YASUDA Masako
Departments of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University
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KOBAYASHI Yasuna
Department of Clinical Pharmacy, Showa University School of Pharmaceutical Sciences
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Suzuki Masanori
Department of Neurosurgery, Nippon Medical School
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Yamamoto Toshinori
Departments Of Clinical Pharmacy And Pharmacognosy School Of Pharmaceutical Sciences Showa Universit
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Yasuda Masako
Department Of Clinical Pharmacy School Of Pharmacy Showa University
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Kohyama Noriko
Department Of Clinical Pharmacy School Of Pharmacy Showa University
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Kohyama Noriko
Department Of Biology Faculty Of Science Ochanomizu University
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Yasuda Masako
Department Of Clinical Pharmacy School Of Pharmaceutical Sciences Showa University
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OHBAYASHI Masayuki
Department of Clinical Pharmacy, School of Pharmacy, Showa University
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YASHIRO Yoshiki
Department of Clinical Pharmacy, School of Pharmacy, Showa University
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FUKUWAKA Sayaka
Department of Clinical Pharmacy, School of Pharmacy, Showa University
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Kobayashi Y
Department Of Clinical Pharmacy School Of Pharmacy Showa University
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Kobayashi Yasuna
Department Of Clinical Pharmacy Showa University School Of Pharmaceutical Sciences
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Fukuwaka Sayaka
Department Of Clinical Pharmacy School Of Pharmacy Showa University
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Yashiro Yoshiki
Department Of Clinical Pharmacy School Of Pharmacy Showa University
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Ohbayashi Masayuki
Department Of Clinical Pharmacy School Of Pharmacy Showa University
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Suzuki Masanori
Department Of Neurosurgery Nippon Medical School
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Suzuki Masanori
Department Of Clinical Pharmacy School Of Pharmacy Showa University
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Suzuki Masanori
Department Of Animal Science Faculty Of Agriculture Tohoku University
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Yamamoto Toshinori
Department Of Pharmacology Medical College Of Oita
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Kobayashi Yasuna
Department of Pharmacotherapy, Division of Clinical Pharmacy, School of Pharmacy, Showa University
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