Functional analysis of tetraspanins(CD9, CD151) in lung fibrosis

• Project/Area Number: 21590992
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Osaka University
• Principal Investigator: TAKEDA Yoshito 大阪大学, 医学系・研究科, 助教 (40452388)
• Co-Investigator(Kenkyū-buntansha): TACHIBANA Isao 大阪大学, 医学系・研究科, 講師 (60324761) ; 川瀬 一郎 大阪大学, 医学系研究科, 教授 (10161324)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 特発性肺線維症 / テトラスパニン / インテグリン、CD9 / CD151 / 肺線維症 / CD9 / 上皮細胞 / 間質性肺炎

Research Abstract

Pulmonary fibrosis(PF) is the process whereby excess fibrous connective tissue forms and characterized by the accumulation of fibrillar collagen. Tetraspanins, key partners of integrins, facilitate the formation of multiple molecular complexes and regulate cell function. We previously reported double deletion of tetraspanin CD9 and CD81 in mice spontaneously developed COPD-like phenotype. The gene functions analyses from DNA Microarray unexpectedly revealed that' connective tissue development and function' were ranked high in CD151 KO lungs. Notably, CD151 KO mice spontaneously developed lung fibrosis with age. Consistently, the level of p-Smad2 in the CD151 KO mice was augmented in the whole lung and in the epithelium. Indeed, deletion of CD151 in alveolar epithelial cells leads to increased p-Smad2 activity on Matrigel, and mesenchymal-like changes. Of interest, expression of CD151 in epithelial cells from IPF patients was downregulated compared with that of healthy controls. Given that CD151 plays a pivotal role to prevent fibrosis through maintaining epithelial integrity, CD151 could be a novel target for PF.

Research Products

• [Journal Article] Tetraspanin CD151 protects against pulmonary fibrosis by maintaining epithelial integrity (2012)
  • Author(s): Kazuyuki Tsujino, Yoshito Takeda, Toru Arai, Yasushi Shintani, Ryosaku Inagaki, Hiroyuki Saiga, Takeo Iwasaki, Satoshi Tetsumoto, Yingji Jin, Shoichi Ihara, Toshiyuki Minami, Mayumi Suzuki, Izumi Nagatomo, Koji Inoue, Hiroshi Kida, Takashi Kijima, Mari Ito, Masanori Kitaichi, Yoshikazu Inoue, Isao Tachibana, Kiyoshi Takeda, Meinoshin Okumura, Martin E. Hemler, Atsushi Kumanogoh
  • Journal Title: Am J Respir Crit Care Med Volume: (in press)
  • Peer Reviewed
• [Journal Article] 4-Hydroxy-2-nonenal induces chronic obstructive pulmonary disease-like histopathologic changes in mice (2012)
  • Author(s): Takimoto T, Yoshida M, Hirata H, Kashiwa Y, Takeda Y, Goya S, Kijima T, Kumagai T, Tachibana I, Kawase I.
  • Journal Title: Biochem Biophys Res Commun Volume: 420(1) Pages: 84-90
  • Peer Reviewed
• [Journal Article] HER2 As Therapeutic Target for Overcoming ATP-Binding Cassette Transporter-Mediated Chemoresistance in Small Cell Lung Cancer (2012)
  • Author(s): Minami T, Kijima T, Otani Y, Kohmo S, Takahashi R, Nagatomo I, Hirata H, Suzuki M, Inoue K, Takeda Y, Kida H, Tachibana I, Kumanogoh A.
  • Journal Title: Mol Cancer Ther Volume: (in press)
  • Peer Reviewed
• [Journal Article] CXCL12 as a biological marker for the diagnosis of tuberculous pleurisy (2012)
  • Author(s): Kohmo S, Kijima T, Mori M, Minami T, Namba Y, Yano Y, Yoneda T, Takeda Y, Kitada S, Yamaguchi T, Tachibana I, Yokota S.
  • Journal Title: Tuberculosis(Edinb) Volume: (in press)
  • Peer Reviewed
• [Journal Article] Early[ 18F] fluorodeoxyglucose positron emission tomography at two days of gefitinib treatment predicts clinical outcome in patients with adenocarcinoma of the lung (2012)
  • Author(s): Takahashi R, Hirata H, Tachibana I, Shimosegawa E, Inoue A, Nagatomo I, Takeda Y, Kida H, Goya S, Kijima T, Yoshida M, Kumagai T, Kumanogoh A, Okumura M, Hatazawa J, Kawase I.
  • Journal Title: Clin Cancer Res Volume: 18(1) Pages: 220-8
  • Peer Reviewed
• [Journal Article] Two cases of leptomeningeal metastases from lung adenocarcinoma which progressed during gefitinib therapy but responded to erlotinib (2012)
  • Author(s): Tetsumoto S, Osa A, Kijima T, Minami T, Hirata H, Takahashi R, Kuhara H, Nagatomo I, Takeda Y, Kida H, Goya S, Tachibana I, Kawase I.
  • Journal Title: Int J Clin Oncol Volume: 17(2) Pages: 155-9
  • NAID: 10030626570
  • Peer Reviewed
• [Journal Article] Favorable response to crizotinib in three patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion-type oncogene-positive non-small cell lung cancer (2011)
  • Author(s): Kijima T, Takeuchi K, Tetsumoto S, Shimada K, Takahashi R, Hirata H, Nagatomo I, Hoshino S, Takeda Y, Kida H, Goya S, Tachibana I, Kawase I.
  • Journal Title: Cancer Sci Volume: 102(8) Pages: 1602-4
  • NAID: 10030242650
  • Peer Reviewed
• [Journal Article] Diminished metastasis in Tetraspanin CD151 Knockout mice (2011)
  • Author(s): Yoshito Takeda, Qinglin Li, Alexander R. Kazarov, Mathieu Epardaud, Kutlu Elpek, Shannon J. Turley, Martin E. Hemler
  • Journal Title: Blood Volume: 118(2) Pages: 464-72
  • Peer Reviewed
• [Journal Article] Safe and successful treatment with erlotinib after gefitinib-induced hepatotoxicity : difference in metabolism as a possible mechanism (2011)
  • Author(s): Takashi Kijima, Tomohito Shimizu, Shinpei Nonen, Mitsugi Furukawa, Yasushi Otani, Toshiyuki Minami, Ryo Takahashi, Haruhiko Hirata, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Sho Goya, Yasushi Fujio, Junichi Azuma, Isao Tachibana, Ichiro Kawase
  • Journal Title: J Clin Oncol Volume: 29(19)
  • Peer Reviewed
• [Journal Article] Involvement of Endothelial Apoptosis Underlying COPD-Like Phenotype in Adiponectin-Null Mice : Implications for Therapy (2011)
  • Author(s): Nakanishi K, Takeda Y(equally first author), Tetsumoto S, Iwasaki T, Tsujino K, Kuhara H, Jin Y, Nagatomo I, Kida H, Goya S, Kijima T, Maeda N, Funahashi T, Shimomura I, Tachibana I, Kawase I.
  • Journal Title: Am J Respir Crit Care Med Volume: 183(9) Pages: 1164-75
  • Peer Reviewed
• [Journal Article] Diminished metastasis in tetraspanin CD151-knockout mice (2011)
  • Author(s): 武田吉人
  • Journal Title: Blood Volume: 118 Issue: 2 Pages: 464-472
  • DOI: 10.1182/blood-2010-08-302240
  • Peer Reviewed
• [Journal Article] Involvement of endothelial apoptosis underlying chronic obstructive pulmonary disease-like phenotype in adiponectin-null mice : implications for therapy (2011)
  • Author(s): 中西香織、武田吉人
  • Journal Title: Am J Respir Criti Care Med Volume: 183 Issue: 9 Pages: 1164-1175
  • DOI: 10.1164/rccm.201007-1091oc
  • Peer Reviewed
• [Journal Article] Cell surface tetraspanin CD9 mediates chemoresistance in small cell lung cancer (2010)
  • Author(s): Kohmo S, Kijima T, Otani Y, Mori M, Minami T, Takahashi R, Nagatomo I, Takeda Y, Kida H, Goya S, Yoshida M, Kumagai T, Tachibana I, Yokota S, Kawase I.
  • Journal Title: Cancer Res Volume: 70(20) Pages: 8025-35
  • Peer Reviewed
• [Journal Article] Tetraspanin CD9 negatively regulates lipopolysaccharide-induced macrophage activation and lung inflammation (2009)
  • Author(s): Mayumi Suzuki, Isao Tachibana, Yoshito Takeda, Ping He, Seigo Minami, Takeo Iwasaki, Sho Goya, Takashi Kijima, Toru Kumagai, Mitsuhiro Yoshida, Tadashi Osaki, and Ichiro Kawase
  • Journal Title: J Immunol Volume: 182(10) Pages: 6485-93
  • Peer Reviewed
• [Journal Article] Tetraspanin CD9 negatively regulates lipopolysaccharide-induced macrophage activation and lung inflammation (2009)
  • Author(s): Suzuki M, Tachibana I, Takeda Y
  • Journal Title: J Immunol. 15 Pages: 6485-93
  • Peer Reviewed
• [Journal Article] COPDモデルとしてのテトラスパニンCD9/CD81ダブルノックアウトマウスの解析 (2009)
  • Author(s): 武田吉人, 立花功, 川瀬一郎
  • Journal Title: International Review of Asthma & COPD 11 Pages: 31-36
• [Journal Article] High frequencies of less differentiated and more proliferative WT1-specific CD8 T cells in bone marrow in tumor-bearing patients : An important role of bone marrow as a secondary lymphoid organ (2009)
  • Author(s): Murao A, Oka Y
  • Journal Title: Cancer Sci. (Equb ahead of print)
  • Peer Reviewed
• [Presentation] Deletion of tetraspanin CD151 in mice spontaneously leads to pulmonary fibrosis with age through epithelial disintegrity (2012)
  • Author(s): Yoshito Takeda, Kazuyuki Tsujino, Isao Tachibana, Atsushi Kumanogoh
  • Organizer: アメリカ胸部疾患学会
  • Place of Presentation: サンフランシスコ米国
  • Year and Date: 2012-05-22
• [Presentation] CD151は肺胞上皮の安定化を介して肺の線維化を制御する (2012)
  • Author(s): 辻野和之、武田吉人、金英姫、鉄本訓史、鈴木真優美、木田博、木島貴志、立花功、熊ノ郷淳
  • Organizer: 日本呼吸器学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2012-04-21
• [Presentation] CD151 KO mice spontaneously develop lung fibrosis, hepatic fibrosis and skin fibrosis via augmented TGF-signaling (2011)
  • Author(s): Yoshito Takeda, Kazuyuki Tsujino, Isao Tachibana, Atsushi Kumanogoh
  • Organizer: FASEB Meeting
  • Place of Presentation: Vermont(USA)
  • Year and Date: 2011-07-22
• [Presentation] CD151 KO mice spontaneously develop lung fibrosis, hepatic fibrosis and skin fibrosis via augmented TGF-β signaling (2011)
  • Author(s): 武田吉人
  • Organizer: FASEB Meeting
  • Place of Presentation: Vermont (USA)(招待講演)
  • Year and Date: 2011-07-22
• [Presentation] COPD患者の末梢血単球における tetraspanin の発現解析 (2009)
  • Author(s): 周博, 武田吉人
  • Organizer: 第49回 日本呼吸器学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-06-21
• [Remarks] 本研究成果は2012年5月17日に全国各誌(毎日、読売、産経、日刊工業新聞)に難病・特発性線維症の鍵物質発見として報道された。
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/imed3/lab_8/index.html
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/imed3/lab_8/index.html
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/imed3/lab_8/index.html