Analysis of the drug-induced lung toxicity in relation to transdifferentiation of type II cells into type I cells and epithelial-mesenchymal transition

• Project/Area Number: 24590195
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Hiroshima University
• Principal Investigator: YUMOTO Ryoko 広島大学, 医歯薬保健学研究院(薬), 講師 (70379915)
• Co-Investigator(Renkei-kenkyūsha): TAKANO Mikihisa 広島大学, 大学院医歯薬保健学研究院, 教授 (20211336)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 薬学 / 薬剤性肺障害 / 肺胞上皮細胞 / II型ーI型分化転換 / 上皮間葉転換 / TGF-β1 / Ⅱ型ーⅠ型分化転換 / II型‐I型分化転換 / 上皮間葉転移

Outline of Final Research Achievements

Transforming growth factor-β1 (TGF-β1) induced epithelial-mesenchymal transition (EMT) in cultured alveolar epithelial cell lines, RLE-6TN cells and A549 cells. Anticancer drugs such as bleomycin and methotrexate also induced EMT-like phenotypical changes in these cell lines. In addition, the involvement of TGF-β1 pathway in the EMT induced by these drugs was suggested. These findings would be helpful for the development of a novel strategy to predict the lung toxicity of drug candidates.

Research Products

• [Journal Article] Transport across the cell membrane and its regulation by vesicular transport, (2015)
  • Author(s): Takano, M., Kawami, M., Yumoto, R.
  • Journal Title: Membrane Volume: 40 Pages: 21-28
  • NAID: 130005069456
  • Peer Reviewed
• [Journal Article] Receptor-mediated endocytosis of macromolecules and strategy to enhance their transport in alveolar epithelial cells. (2015)
  • Author(s): Takano, M., Aoki, A., Kawami, M. and Yumoto, R.
  • Journal Title: Expert Opinion on Drug Delivery Volume: 13 Issue: 5 Pages: 331-337
  • DOI: 10.1517/17425247.2015.992778
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of TGF-β1-and drug-induced epithelial-mesenchymal transition in cultured alveolar epithelial cell line RLE/Abca3 (2015)
  • Author(s): Takano, M., Yamamoto, C., Yamaguchi, K., Kawami, M. and Yumoto, R.
  • Journal Title: Drug Metab. Pharmacokinet. Volume: 30 Issue: 1 Pages: 111-118
  • DOI: 10.1016/j.dmpk.2014.10.007
  • NAID: 50014415988
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Modulation of P-glycoprotein function and multidrug resistance in cancer cells by Thai plant extracts. (2014)
  • Author(s): Takano, M., Kakizoe, S., Kawami M., Nagai J., Patanasethanont, D., Sripanidkulchai B., Yumoto, R.
  • Journal Title: Pharmazie Volume: 69 Pages: 823-828
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fatty acid-bearing albumin but not fatty acid-depleted albumin induces HIF-1 activation in human renal proximal tubular epithelial cell line HK-2. (2014)
  • Author(s): Nagai, J., Yamamoto, A., Katagiri, Y., Yumoto, R., Takano, M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 450 Issue: 1 Pages: 476-481
  • DOI: 10.1016/j.bbrc.2014.05.146
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Folic acid-modified methotrexate-conjugated PEGylated poly(e-caprolactone) nanoparticles for targeted delivery. (2014)
  • Author(s): Issarachot, O., Suksiriworapong, J., Takano, M., Yumoto, R. and Junyapraser, V.B.
  • Journal Title: J. Nanopart. Res. Volume: 16 Issue: 2 Pages: 2276-2290
  • DOI: 10.1007/s11051-014-2276-7
  • Peer Reviewed / Open Access
• [Journal Article] Enhancing Effect of Poly(amino acid)s on Albumin Uptake in Human Lung Epithelial A549 Cells (2013)
  • Author(s): Yumoto, R., Suzuka, S., Nishimoto, S., Nagai, J. and Takano, M.
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 28 Issue: 6 Pages: 497-503
  • DOI: 10.2133/dmpk.DMPK-13-RG-028
  • NAID: 130004463336
  • ISSN: 1347-4367, 1880-0920
  • Peer Reviewed / Open Access
• [Journal Article] Introduction of a single transport gene ABCA3 directs RLE-6TN to more typeII-like alveolar epithelial cells. (2013)
  • Author(s): Takano, M., Yamamoto, C., Sambuichi K., Oda, K., Nagai, J., Shimamoto, A., Tahara, H. and Yumoto, R.
  • Journal Title: Membrane Volume: 38 Pages: 246-253
  • Peer Reviewed
• [Journal Article] Expression and function of PEPT2 during transdifferentiation of alveolar epithelial cells (2013)
  • Author(s): Takano, M., Horiuchi, T., Sasaki, Y., Kato Y., Nagai, J. and Yumoto, R.
  • Journal Title: Life Sciences Volume: 93 Issue: 17 Pages: 630-636
  • DOI: 10.1016/j.lfs.2013.08.008
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of insulin transport by D-glucose in alveolar epithelial cells. (2013)
  • Author(s): Oda, K., Yumoto, R., Nagai, J. and Takano, M.
  • Journal Title: Biomedicine＆Aging Pathology Volume: 3 Pages: 247-252
  • Peer Reviewed
• [Journal Article] Flow Cytometry Analysis of Cancer Cell Death Induced by the Extract of Thai Plant <i>Ellipeiopsis cherrevensis</i> (2013)
  • Author(s): Ryoko Yumoto
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 28 Issue: 2 Pages: 159-163
  • DOI: 10.2133/dmpk.DMPK-12-NT-056
  • NAID: 130004933522
  • ISSN: 1347-4367, 1880-0920
  • Peer Reviewed / Open Access
• [Journal Article] Endocytic Uptake of FITC-albumin by Human Alveolar Epithelial Cell Line A549 (2012)
  • Author(s): Yumoto, R., Suzuka, S., Oda, K., Imaoka, H. and Nagai, J. and Takano, M.
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 27 Issue: 3 Pages: 336-343
  • DOI: 10.2133/dmpk.DMPK-11-RG-127
  • NAID: 130004463255
  • ISSN: 1347-4367, 1880-0920
  • Peer Reviewed
• [Journal Article] Enhancement Effect of Poly(amino acid)s on Insulin Uptake in Alveolar Epithelial Cells (2012)
  • Author(s): Oda, K., Yumoto, R., Nagai, J., Katayama, H. and Takano, M.
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 27 Issue: 6 Pages: 570-578
  • DOI: 10.2133/dmpk.DMPK-12-RG-002
  • NAID: 130004933511
  • ISSN: 1347-4367, 1880-0920
  • Peer Reviewed
• [Journal Article] Effect of cigarette smoke extract on insulin transport in alveolar epithelial cell line A549 (2012)
  • Author(s): Takano, M. Horiuchi, T., Nagai, J. and Yumoto R.
  • Journal Title: Lung Volume: 190 Issue: 6 Pages: 651-659
  • DOI: 10.1007/s00408-012-9413-9
  • Peer Reviewed
• [Journal Article] Gadolinium modulates gentamicin uptake via an endocytosis-independent pathway in HK-2 human renal proximal tubular cell line. (2012)
  • Author(s): Takeshi Sawada
  • Journal Title: European Journal of Pharmacology Volume: 84(1-3) Issue: 1-3 Pages: 146-153
  • DOI: 10.1016/j.ejphar.2012.03.030
  • Peer Reviewed
• [Presentation] ヒト肺上皮由来H441細胞におけるペプチドトランスポーターPEPT2の発現と機能の解析 (2015)
  • Author(s): 杉本奈津美、湯元良子、EHRHARDT Carsten、高野幹久
  • Organizer: 日本薬学会 第135年会
  • Place of Presentation: 神戸学院大学、兵庫医療大学
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 新たなマイクロアレイを用いた薬剤性肺障害予測システムの開発 (2015)
  • Author(s): 青木彩子、山口晃輝、山本千恵子、湯元良子、大島宏之、高野幹久
  • Organizer: 日本薬学会 第135年会
  • Place of Presentation: 神戸学院大学、兵庫医療大学
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 喫煙による肺胞上皮II型細胞のペプチドトランスポーターPept2の機能変動 (2014)
  • Author(s): 佐々木佳宏、岸本 海、湯元良子、高野幹久
  • Organizer: 膜シンポジウム2014
  • Place of Presentation: 神戸大学百年記念館
  • Year and Date: 2014-11-26 – 2014-11-27
• [Presentation] Evaluation of epithelial-mesenchymal transition associated with methotrexate-induced injury in cultured human alveolar epithelial cell line (2014)
  • Author(s): Masashi Kawami, Mioka Miyamoto, Ryoko Yumoto, Mikihisa Takano
  • Organizer: 第8回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 熊本大学薬学部 宮本記念館
  • Year and Date: 2014-11-15 – 2014-11-16
• [Presentation] 培養肺胞上皮細胞RLE/Abca3を用いた薬剤誘発性上皮間葉転換の解析 (2014)
  • Author(s): 山口晃輝、湯元良子、高野幹久
  • Organizer: 第53回日本薬学会・日本薬剤師会・日本病院薬剤師会 中国四国支部学術大会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-11-08 – 2014-11-09
• [Presentation] TGF-&#61538;および肺障害性薬物による肺胞上皮Ⅱ型細胞の上皮間葉転換とmiRNAの発現変動 (2014)
  • Author(s): 猫本千波、山口晃輝、湯元良子、高野幹久
  • Organizer: 第53回日本薬学会・日本薬剤師会・日本病院薬剤師会 中国四国支部学術大会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-11-08 – 2014-11-09
• [Presentation] 培養肺胞上皮細胞A549におけるメトトレキサートの輸送特性解析 (2014)
  • Author(s): 宮本未緒花、川見昌史、湯元良子、高野幹久
  • Organizer: 第53回日本薬学会・日本薬剤師会・日本病院薬剤師会 中国四国支部学術大会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-11-08 – 2014-11-09
• [Presentation] Effect of cigarette smoke extract on PEPT2 function in alveolar epithelial cells (2014)
  • Author(s): Yumoto, R., Sasaki, Y., Takano, M.
  • Organizer: JSSX-ISSX Joint Meeting in San Francisco
  • Place of Presentation: the Hilton San Francisco Union Square Hotel
  • Year and Date: 2014-10-18 – 2014-10-23
• [Presentation] Comparison of epithelial-mesenchymal transition induced by TGF-β1 and methotrexate in human alveolar epithelial cell line A549 (2014)
  • Author(s): Kawami, M., Miyamoto, M., Yumoto, R., Takano, M.
  • Organizer: JSSX-ISSX Joint Meeting in San Francisco
  • Place of Presentation: the Hilton San Francisco Union Square Hotel
  • Year and Date: 2014-10-18 – 2014-10-23
• [Presentation] Transport of nicotine, an organic cation, in alveolar epithelial cells (2014)
  • Author(s): Nagahiro, M., Sasaki, Y., Yumoto, R., Takano, M.
  • Organizer: JSSX-ISSX Joint Meeting in San Francisco
  • Place of Presentation: the Hilton San Francisco Union Square Hotel
  • Year and Date: 2014-10-18 – 2014-10-23
• [Presentation] 肺胞上皮細胞の分化転換に伴うペプチドトランスポーターの発現・機能変化と喫煙関連物質の影響 (2014)
  • Author(s): 湯元良子、佐々木佳寛、岸本海、永井純也、高野幹久
  • Organizer: 医療薬学フォーラム2014/第22回クリニカルファーマシーシンポジウム
  • Place of Presentation: ビッグサイトTFTホール
  • Year and Date: 2014-06-28 – 2014-06-29
• [Presentation] 肺障害性薬物によるヒト由来培養肺胞上皮細胞A549の上皮間葉転換の解析 (2014)
  • Author(s): 川見昌史、山本千恵子、山口晃輝、永井純也、湯元良子、高野幹久
  • Organizer: 日本薬剤学会第29年会
  • Place of Presentation: 大宮ソニックシティビル
  • Year and Date: 2014-05-20 – 2014-05-22
• [Presentation] 肺胞上皮細胞の分化転換と薬物輸送機能 (2014)
  • Author(s): 高野 幹久、湯元 良子
  • Organizer: 日本薬剤学会第29年会
  • Place of Presentation: 大宮ソニックシティビル
  • Year and Date: 2014-05-20 – 2014-05-22
  • Invited
• [Presentation] ヒト肺上皮由来H441細胞の基本特性とペプチドトランスポーターPEPT2の発現・機能 (2014)
  • Author(s): 杉本奈津美、湯元良子、山本千恵子、永井純也、Carsten Ehrhardt、高野幹久
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本大学黒髪キャンパス
• [Presentation] Expression and function of a peptide transporter PEPT2 in alveolar epithelial cells in culture (2014)
  • Author(s): Ｒｙｏｋｏ Ｙｕｍｏｔｏ, Natsumi Sugimoto, Yoshihiro Sasaki, Chieko Yamamoto, Junya Nagai, Carsten Ehrhardt, Mikihisa Takano
  • Organizer: The 5th FIP PSWC in Melbourne
  • Place of Presentation: Melbourne Convention and Exhibition Centre （オーストラリア）
• [Presentation] 肺胞上皮細胞におけるPeptide Transporter 2の発現・機能と喫煙関連物質の影響 (2014)
  • Author(s): 佐々木佳寛、岸本海、永井純也、湯元良子、高野幹久
  • Organizer: 日本膜学会第36年会
  • Place of Presentation: 早稲田大学西早稲田キャンパス
• [Presentation] Expression and function of P-glycoprotein in alveolar epithelial cells and its modulation by cigarette smoke extract (2013)
  • Author(s): Ryoko Yumoto, Yoshihiro Sasaki, Taishi Horiuchi, Yuki Kato, Umi Kishimoto, Junya Nagai, Mikihisa Takano
  • Organizer: 73th FIP World Congress in Dublin
  • Place of Presentation: Convention Centre Dublin （アイルランド）
• [Presentation] Analysis of drug-induced epithelial mesenchymal transition in cultured alveolar epithelial cell line RLE/Abca3 (2013)
  • Author(s): Chieko Yamamoto, kouki Yamaguchi, Junya Nagai, Ryoko Yumoto and Mikihisa Takano
  • Organizer: 28th JSSX Annual Meting in Tokyo
  • Place of Presentation: Tower Hall Funabori
• [Presentation] 肺胞上皮細胞の上皮間葉転換と薬剤性肺傷害予測法の構築 (2013)
  • Author(s): 山口晃輝、三分一圭祐、山本千恵子、永井純也、湯元良子、高野幹久
  • Organizer: 日本薬剤学会第28年会
  • Place of Presentation: ウインクあいち
• [Presentation] 喫煙者における経肺投与インスリンのバイオアベイラビリティ上昇機構の解明 (2013)
  • Author(s): 岸本 海、佐々木佳寛、山本千恵子、堀内大士、永井純也、湯元良子、高野幹久
  • Organizer: 医療薬学フォーラム2013/第21回クリニカルファーマシーシンポジウム
  • Place of Presentation: 石川県立音楽堂
• [Presentation] 糖尿病患者における経肺投与インスリンのバイオアベイラビリティ上昇の機構解明 (2013)
  • Author(s): 西本沙央里、小田啓祐、永井純也、湯元良子、高野幹久
  • Organizer: 医療薬学フォーラム2013/第21回クリニカルファーマシーシンポジウム
  • Place of Presentation: 石川県立音楽堂
• [Presentation] Phenotypical changes of RLE-6TN alveolar epithelial cell line by transfection with Abca3 gene (2012)
  • Author(s): Mikihisa Takano
  • Organizer: 18th North American Regional ISSX Meeting
  • Place of Presentation: Hilton Anatol Hotel in Dallas (米国)
• [Presentation] Transdifferentiation and transport function of alveolar epithelial cells (2012)
  • Author(s): MIkihisa Takano
  • Organizer: International Symposium on Epithelial Barrier and Transport 2012
  • Place of Presentation: Ritsumeikan University
  • Invited
• [Presentation] Induction of phonotypical changes by transfection of a transporter gene Abca3 in cultured alveolar epithelial cell line RLE-6TN (2012)
  • Author(s): Chieko Yamamoto
  • Organizer: 27th JSSX Annual Meeting in Tokyo
  • Place of Presentation: Tower Hall Funabori (東京）
• [Presentation] 肺胞上皮細胞のII型‐I型分化転換と生体膜トランスポーターの発現・機能 (2012)
  • Author(s): 湯元 良子
  • Organizer: 日本膜学会第34年会
  • Place of Presentation: 早稲田大学 西早稲田キャンパス63号館
• [Presentation] 肺胞上皮細胞のII型-I型分化転換とオリゴペプチドトランスポーターPEPTの発現・機能 (2012)
  • Author(s): 堀内 大士
  • Organizer: 日本薬剤学会第27年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] 肺胞上皮細胞におけるアルブミンの輸送とその制御 (2012)
  • Author(s): 湯元 良子
  • Organizer: 膜シンポジウム2012
  • Place of Presentation: 神戸大学百年記念館