Analyses of alveolar epithelial injury via lipid-related stress in mammalian target of rapamycin inhibitor-induced lung disease
Project/Area Number |
15K19433
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
Respiratory organ internal medicine
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Research Institution | Nippon Medical School |
Principal Investigator |
kokuho nariaki 日本医科大学, 大学院医学研究科 呼吸器内科学, 特別研究生 (90595167)
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Project Period (FY) |
2015-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | mTOR阻害薬肺障害 / Temsirolimus / 脂質代謝ストレス / Pioglitazone / PPAR-γ / 脂質異常症 / 高脂血症 / mTOR阻害薬 / 上皮障害 / 肺胞サーファクタント / 肺胞上皮傷害 / 肺脂肪毒性 / mTOR阻害薬 / 肺障害 / バイオマーカー |
Outline of Final Research Achievements |
Although mammalian target of rapamycin inhibitors (mTORi) are used to treat various malignancies, they frequently induce active alveolitis and dyslipidemia. Abnormal lipid metabolism affects alveolar surfactant function and results in pulmonary disorders; however, the pathophysiology of lung injury and its relationship with lipid metabolism remain unknown. We investigated the relationship between lipid metabolism and alveolar epithelial injury, focusing on peroxisome proliferator-activated receptor-γ (PPAR-γ) as a lipid stress-related factor in mTORi-induced lung injury. In conclusion, the pathogenesis of mTORi-induced lung disease may be involved in alveolar epithelial injury, via lipid metabolic stress associated with downregulated PPAR-γ expression. Focusing on the relationship between lipid metabolic stress and alveolar epithelial injury represents a potentially novel approach to the study of pulmonary damage.
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Academic Significance and Societal Importance of the Research Achievements |
mTOR阻害薬(mTOR-i)は抗腫瘍作用を有する薬剤ではあるが、 薬剤性肺障害を高頻度(約30%)に発症すると報告されている。本研究においては、mTOR-iによる薬剤性肺障害の病態解明を目的とし、同薬剤による脂質代謝への影響と肺胞上皮への作用について、特に脂質関連因子(PPAR-γ)に着目して検討を行った。 mTORi肺障害の病態は局所性ないし全身性の脂質代謝ストレスを介した肺胞上皮傷害であり、PPAR-γの発現低下が肺内脂質の恒常性の破綻と炎症を惹起することで、上皮傷害に関与したと考えられた。脂質代謝ストレスと肺胞上皮傷害の関係性は、今後の肺障害研究において新たな糸口になると考えられた。
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Report
(5 results)
Research Products
(28 results)
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[Journal Article] Prognostic Factors in the Acute Exacerbation of Idiopathic Pulmonary Fibrosis: A Retrospective Single-center Study2018
Author(s)
Atsumi K, Saito Y, Kuse N, Kobayashi K, Tanaka T, Kashiwada T, Inomata M, Kokuho N, Hayashi H, Kamio K, Fujita K, Abe S, Azuma A, Kubota K, Gemma A.
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Journal Title
Internal Medicine
Volume: 57
Issue: 5
Pages: 655-661
DOI
NAID
ISSN
0918-2918, 1349-7235
Related Report
Peer Reviewed
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[Journal Article] XPLN is modulated by HDAC inhibitors and negatively regulates SPARC expression by targeting mTORC2 in human lung fibroblasts2017
Author(s)
Koichiro Kamio, Arata Azuma, Jiro Usuki, Kuniko Matsuda, Minoru Inomata, Nobuhiko Nishijima, Shioto Itakura, Hiroki Hayashi, Takeru Kashiwada, Nariaki Kokuho, Kenichiro Atsumi, Tomoyoshi Yamaguchi, Kazue Fujita, Yoshinobu Saito, Shinji Abe, Kaoru Kubota, Akihiko Gemma
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Journal Title
Pulmonary Pharmacology & Therapeutics
Volume: 44
Pages: 61-69
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Role of canstatin in early fibrotic lesions of idiopathic interstitial pneumonias and migration of lung fibroblasts2016
Author(s)
Urushiyama H, Terasaki Y, Nagasaka S, Kokuho N, Terasaki M, Kunugi S, Mikami Y, Noguchi S, Horie M, Nagahama K, Yamauchi Y, Shimizu A, Nagase T
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Journal Title
Int J Clin Exp Pathol
Volume: 9
Pages: 12714-12722
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis: a case report and literature review.2016
Author(s)
Kokuho N, Terasaki Y, Urushiyama H, Terasaki M, Kunugi S, Morimoto T, Azuma A, Usuda J, Gemma A, Eishi Y, Shimizu A.
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Journal Title
Hum Pathol.
Volume: 51
Pages: 57-63
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Nintedanib modulates surfactant protein-D expression in A549 human lung epithelial cells via the c-Jun N-terminal kinase-activator protein-1 pathway.2015
Author(s)
Kamio K, Usuki J, Azuma A, Matsuda K, Ishii T, Inomata M, Hayashi H, Kokuho N, Fujita K, Saito Y, Miya T, Gemma A.
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Journal Title
Pulm Pharmacol Ther.
Volume: 5539(15)
Pages: 00036-00036
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Presentation] 当院における抗ARS抗体陽性間質性肺炎の臨床病理学的検討2016
Author(s)
柏田建, 根井貴仁, 齋藤好信,中山幸治, 渥美健一郎, 林宏紀, 藤田和恵, 久保田馨, 吾妻安良太, 國保成暁, 功刀しのぶ, 寺崎泰弘, 弦間昭彦
Organizer
日本呼吸器学会学術講演会(第56回)
Place of Presentation
京都国際会館
Year and Date
2016-04-08
Related Report
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[Presentation] 破骨細胞様巨細胞を伴う子宮平滑筋肉腫の1例.2015
Author(s)
寺崎美佳, 寺崎泰弘, 米山剛一, 長濱清隆, 若松恭子, 桑原尚美, 功刀しのぶ, 梶本雄介, 漆山博和, 國保茂暁, 竹下俊行, 清水 章
Organizer
日本病理学会総会(第104回),
Place of Presentation
名古屋国際会議場
Year and Date
2015-04-30
Related Report
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