Study on the molecular and cellular markers associated with clinical phenotype of COPD

• Project/Area Number: 24591139
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Jikei University School of Medicine
• Principal Investigator: NAKAYAMA KATSUTOSHI 東京慈恵会医科大学, 医学部, 准教授 (40321989)
• Co-Investigator(Renkei-kenkyūsha): ISHIKAWA Takeo 東京慈恵会医科大学, 医学部, 助教 (60366200) ; ARAYA Jun 東京慈恵会医科大学, 医学部, 准教授 (90468679)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 慢性閉塞性肺疾患 / フェノタイプ / 肺機能急速減衰 / 難治化増悪 / 全身性炎症 / 酸化ストレス / 喘息COPDオーバーラップ症候群 / ヘムオキシゲナーゼ-1 / 喘息合併COPD / 増悪 / クラム陰性桿菌 / 細菌定着 / Multiplex Real-time PCR / 肺機能 / 肺機能早期減衰 / TNF-alpha

Outline of Final Research Achievements

We studied the molecular and cellular markers associated with important clinical phenotypes of chronic pulmonary disease (COPD), “rapid decline of pulmonary function” and “refractory exacerbation of COPD”. As the results, rapid decline is associated with expansion of systemic inflammation with serum TNF-a level elevation. Refractory exacerbation of COPD is associated with triggering infection with enteric or non-fermenting Gram negative rods.
Furthermore, we evaluated systemic inflammation and oxidative stress among COPD, bronchial asthma (BA), and overlap of them (ACOS). Systemic inflammation is significantly higher in COPD/ACOS than BA, because of smoking-induced pathogenesis. Oxidative stress is significantly higher in COPD than BA/ACOS, because of reduction of anti-oxidative activity in COPD.

Research Products

• [Journal Article] PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis. (2015)
  • Author(s): Ito S, Araya J, Kurita Y, Kobayashi K, Takasaka N, Yoshida M, Hara H, Minagawa S, Wakui H, Fujii S, Kojima J, Shimizu K, Numata T, Kawaishi M, Odaka M, Morikawa T, Harada T, Nishimura SL, Kaneko Y, Nakayama K, Kuwano K.
  • Journal Title: Autophagy Volume: 11 Pages: 547-559
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Relation between recurrence of tuberculosis and transitional changes in IFN-γ release assays. (2015)
  • Author(s): Kaneko Y, Nakayama K, Kinoshita A, Kurita Y, Odashima K, Saito Z, Yoshii Y, Horikiri T, Seki A, Seki Y, Takeda H, Kuwano K.
  • Journal Title: Am J Respir Crit Care Med Volume: 191 Issue: 4 Pages: 480-483
  • DOI: 10.1164/rccm.201409-1590le
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SIRT6のよるオートファジー制御と気道上皮細胞老化 (2015)
  • Author(s): 高坂直樹, 荒屋潤, 栗田裕輔, 小林賢司, 伊藤三郎, 小島淳, 原弘道, 清水健一郎, 沼田尊功, 河石真, 金子由美, 中山勝敏, 桑野和善.
  • Journal Title: 分子呼吸器病 Volume: 19 Pages: 112-114
• [Journal Article] Lung adenocarcinoma complicated by Trousseau's syndrome successfully treated by a combination of anticoagulant therapy and chemotherapy. (2014)
  • Author(s): Yoshii Y, Numata T, Ishitobi W, Takahashi N, Wakui H, Kojima J, Shimizu K, Hara H, Ishikawa T, Kawaishi M, Saito K, Araya J, Kaneko Y, Nakayama K, Kuwano K.
  • Journal Title: Intern Med Volume: 53 Pages: 1835-1839
  • NAID: 130004678396
  • Peer Reviewed
• [Journal Article] 中等症/重症のCOPD 患者に対するブデソニド/ホルメテロール配合剤の上乗せあるいは変更が有効であった3 症例の経験. (2014)
  • Author(s): 金子由美, 橋本典生, 中山勝敏, 桑野和善.
  • Journal Title: 呼吸 Volume: 33 Pages: 1162-1166
  • Peer Reviewed
• [Journal Article] 【特集 COPD を改めて問う】 治療：気管支拡張薬の限界. (2014)
  • Author(s): 中山勝敏, 清水健一郎, 小島淳, 桑野和善.
  • Journal Title: THE LUNGperspectives Volume: 22 Pages: 136-143
• [Journal Article] 【特集 すぐ役立つ 呼吸器薬の標準的使い方】 ＣＯＰＤ増悪期の治療 (2014)
  • Author(s): 小島淳, 中山勝敏, 桑野和善.
  • Journal Title: Medicina Volume: 51 Pages: 1854-1857
• [Journal Article] 治療薬選択に難渋した慢性壊死性肺アスペルギルス症の1例 (2014)
  • Author(s): 小島淳, 河石真, 荒屋潤, 中山勝敏, 桑野和善.
  • Journal Title: 日本胸部臨床 Volume: 73 Pages: 446-454
  • Peer Reviewed
• [Journal Article] 肺の気腫化と線維化 (2014)
  • Author(s): 桑野和善, 荒屋潤, 中山勝敏.
  • Journal Title: 呼吸 Volume: 33 Pages: 346-352
• [Journal Article] Autophagy induction by SIRT6 through attenuation of insulin-like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence. (2014)
  • Author(s): Takasaka N, Nakayama K, et al.
  • Journal Title: J Immunol Volume: 192 Issue: 3 Pages: 958-968
  • DOI: 10.4049/jimmunol.1302341
  • Peer Reviewed / Open Access
• [Journal Article] 慢性閉塞性肺疾患の肺胞マクロファージにおけるAIMの発現. (2014)
  • Author(s): 小島淳, 中山勝敏, 他
  • Journal Title: 分子呼吸器病学 Volume: 18 Pages: 163-165
• [Journal Article] 治療抵抗性の急速進行性間質性肺炎を合併したClinically amyopathic dermatomyositis (CADM)の1剖検例. (2014)
  • Author(s): 清水健一郎, 中山勝敏, 他
  • Journal Title: 慈恵医大誌 Volume: 129 Pages: 11-17
• [Journal Article] Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence. (2013)
  • Author(s): Hara H, Araya J, Ito S, Kobayashi K, Takasaka N, Yoshii Y, Wakui H, Kojima J, Shimizu K, Numata T, Kawaishi M, Kamiya N, Odaka M, Morikawa T, Kaneko Y, Nakayama K, Kuwano K.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: 305(10) Issue: 10 Pages: L737-L746
  • DOI: 10.1152/ajplung.00146.2013
  • Peer Reviewed
• [Journal Article] 【特集 呼吸器疾患の増悪を考える】 増悪時の呼吸機能変化. (2013)
  • Author(s): 中山勝敏, 他
  • Journal Title: THE LUNG-perspectives Volume: 21 Pages: 229-236
• [Journal Article] Apoptosis inhibitor of macrophage (AIM) expression in alveolar macrophages in COPD. (2013)
  • Author(s): Jun Kojima
  • Journal Title: Respiratory Research Volume: 14 Issue: 1 Pages: 30-39
  • DOI: 10.1186/1465-9921-14-30
  • Peer Reviewed
• [Journal Article] Insufficient autophagy in idiopathic pulmonary fibrosis. (2013)
  • Author(s): Araya J, et al.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: Jan 1;304(1): Issue: 1 Pages: L56-L69
  • DOI: 10.1152/ajplung.00213.2012
  • Peer Reviewed
• [Journal Article] Involvement of creatine kinase B in cigarette smoke induced-bronchial epithelial cell senescence. (2012)
  • Author(s): Hara H, Nakayama K, et al
  • Journal Title: Am J Respir Cell Mol Biol Volume: 46 Issue: 3 Pages: 306-312
  • DOI: 10.1165/rcmb.2011-0214oc
  • Peer Reviewed
• [Journal Article] Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease. (2012)
  • Author(s): Fujii S, Nakayama K, et al
  • Journal Title: OncoImmunology Volume: 1 Pages: 630-641
  • Peer Reviewed
• [Presentation] Viral and bacterial etiologies in acute exacerbation of COPD detected using a multiplex real-time polymerase chain reaction (2014)
  • Author(s): Kenichiro Shimizu, Yutaka Yoshii, Miyuki Morozumi, Naoko Chiba, Kimiko Ubukata, Hironori Uruga, Shigeo Hanada, Saburo Ito, Naoki Takasaka, Hiromichi Hara, Takanori Numata, Makoto Kawaishi, Jun Araya, Yumi Kaneko, Katsutoshi Nakayama, Kazuyoshi Kuwano.
  • Organizer: European Respiratory Society International Congress 2014
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-09-06 – 2014-09-10
• [Presentation] Mitophagic regulation of myofibroblast differentiation in lung fibroblasts (2014)
  • Author(s): Kenji Kobayashi, Jun Araya, Hiromichi Hara, Yusuke Kurita, Saburo Ito, Naoki Takasaka, Satoko Fujii, Shunsuke Minagawa, Jun Kojima, Takanori Numata, Kenichiro Shimizu, Makoto Kawaishi, Yumi Kaneko, Toshiaki Morikawa, Katsutoshi Nakayama, Kazuyoshi Kuwano.
  • Organizer: European Respiratory Society International Congress 2014
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-09-06 – 2014-09-10
• [Presentation] PINK1-Parkin pathway-mediated mitophagy is involved in cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBEC) (2014)
  • Author(s): Saburo Ito, Jun Araya, Hiromichi Hara, Yusuke Kurita, Kenji Kobayashi, Naoki Takasaka, Hiroshi Wakui, Yutaka Yoshii, Shunsuke Minagawa, Jun Kojima, Takanori Numata, Kenichiro Shimizu, Makoto Kawaishi, Yumi Kaneko, Katsutoshi Nakayama, Kazuyoshi Kuwano.
  • Organizer: European Respiratory Society International Congress 2014
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-09-06 – 2014-09-10
• [Presentation] Transcription factor EB (TFEB) regulates cigarette smoke extract (CSE)-induced cellular senescence (2014)
  • Author(s): Yusuke Kurita, Jun Araya, Hiromiti Hara, Kenji Kobayashi, Saburo Ito, Naoki Takasaka, Hiroshi Wakui, Yutaka Yoshii, Shunsuke Minagawa, Jun Kojima, Takanori Numata, Kenichiro Shimizu, Makoto Kawaishi, Yumi Kaneko, Katsutoshi Nakayama, Kazuyoshi Kuwano.
  • Organizer: European Respiratory Society International Congress 2014
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-09-06 – 2014-09-10
• [Presentation] Metformin inhibits TGF-b-induced myofibroblast differentiation through AMPK activation (2014)
  • Author(s): Naoki Takasaka, Jun Araya, Yusuke Kurita, Kenji Kobayashi, Saburo Ito, Hiroshi Wakui, Yutaka Yoshii, Shunsuke Minagawa, Jun Kojima, Hiromichi Hara, Takanori Numata, Kenichiro Shimizu, Makoto Kawaishi, Yumi Kaneko, Katsutoshi Nakayama, Kazuyoshi Kuwano.
  • Organizer: European Respiratory Society International Congress 2014
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-09-06 – 2014-09-10
• [Presentation] Multiplex real-time polymerase chain reaction is useful in diagnosing pathogens causing community-acquired pneumonia including atypical bacteria and viruses (2014)
  • Author(s): Yutaka Yoshii, Kenichiro Shimizu, Miyuki Morozumi, Naoko Chiba, Kimiko Ubukata, Hironori Uruga, Shigeo Hanada, Kazuma Kishi, Hiroshi Wakui, Shunsuke Minagawa, Jun Kojima, Hiromichi Hara, Takanori Numata, Makoto Kawaishi, Jun Araya, Yumi Kaneko, Katsutoshi Nakayama, Kazuyoshi Kuwano.
  • Organizer: European Respiratory Society International Congress 2014
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-09-06 – 2014-09-10
• [Presentation] COPDにおけるオートファジー (2014)
  • Author(s): 中山勝敏
  • Organizer: 東京呼吸器疾患懇話会
  • Place of Presentation: 目黒雅叙園
  • Year and Date: 2014-07-11
  • Invited
• [Presentation] オートファジーによる筋線維芽細胞分化の制御 (2014)
  • Author(s): 小林賢司，荒屋潤，原弘道，栗田裕輔，伊藤三郎，高坂直樹，皆川俊介，河石真，森川利昭，中山勝敏，桑野和善．
  • Organizer: 第５４回 日本呼吸器学会 学術講演会
  • Place of Presentation: 大阪国際会議場、リーガロイヤルホテル
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] 網羅的real-time PCR法を用いた成人Mycoplasma pneumoniae呼吸器感染症の臨床的検討 (2014)
  • Author(s): 吉井悠，清水健一郎，宇留賀 公紀，花田豪郎，岸一馬，河石真，荒屋潤，中山勝敏，諸角美由紀，千葉菜穂子，生方公子，桑野和善．
  • Organizer: 第５４回 日本呼吸器学会 学術講演会
  • Place of Presentation: 大阪国際会議場、リーガロイヤルホテル
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] 画像上肺MAC症が疑われた症例に実施した抗GPL-core IgA抗体検査の検討 (2014)
  • Author(s): 沼田尊功，高橋直子，保坂悠介，渡邊直昭，吉井悠，和久井大，皆川俊介，小島淳，原弘道，清水健一郎，河石真，荒屋潤，金子由美，中山勝敏，桑野和善．
  • Organizer: 第５４回 日本呼吸器学会 学術講演会
  • Place of Presentation: 大阪国際会議場、リーガロイヤルホテル
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] Parkin誘導性ﾏｲﾄﾌｧｼﾞｰによる喫煙刺激気道上皮細胞老化の制御 (2014)
  • Author(s): 伊藤三郎，荒屋潤，栗田裕輔，小林賢司，高坂直樹，皆川俊介，小島淳，原弘道，沼田尊功，清水健一郎，河石真，金子由美，中山勝敏，桑野和善．
  • Organizer: 第５４回 日本呼吸器学会 学術講演会
  • Place of Presentation: 大阪国際会議場、リーガロイヤルホテル
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] 進行非小細胞肺癌に対するPemetrexed治療後のS-1単剤療法の検討 (2014)
  • Author(s): 河石真，和久井大，吉井悠，栗田裕輔，小林賢司，伊藤三郎，高坂直樹，皆川俊介，小島淳，清水健一郎，沼田尊功，原弘道，金子由美，荒屋潤，中山勝敏，桑野和善．
  • Organizer: 第５４回 日本呼吸器学会 学術講演会
  • Place of Presentation: 大阪国際会議場、リーガロイヤルホテル
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] IgG4関連疾患による続発性肺胞蛋白症の1例 (2014)
  • Author(s): 小島淳，荒屋潤，和久井大，原弘道，沼田尊功，清水健一郎，河石真，金子由美，中山勝敏，桑野和善．
  • Organizer: 第５４回 日本呼吸器学会 学術講演会
  • Place of Presentation: 大阪国際会議場、リーガロイヤルホテル
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] Multiplex PCRによるCOPDの急性増悪に関与する病原微生物検出 (2014)
  • Author(s): 清水健一郎，吉井悠，宇留賀 公紀，花田豪郎，岸一馬，河石真，荒屋潤，中山勝敏，諸角美由紀，千葉菜穂子，生方公子，桑野和善．
  • Organizer: 第５４回 日本呼吸器学会 学術講演会
  • Place of Presentation: 大阪国際会議場、リーガロイヤルホテル
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] Special Lecture: Molecular mechanism and clinical conditions in COPD -cigarette smoke-induced cellular senescence and autophagy-. (2013)
  • Author(s): Nakayama K.
  • Organizer: Autumn Congress of Korea Academy of Tuberculosis and Respiratory Disease (KATRD).
  • Place of Presentation: Seol
  • Invited
• [Presentation] COPDの増悪 (2013)
  • Author(s): 中山勝敏
  • Organizer: 第53回臨床呼吸機能講習会(日本呼吸器学会) イブニングセミナー
  • Place of Presentation: 京王プラザホテル, 東京
  • Invited
• [Presentation] The effct of comorbidity, systemic inflammation, and oxidative stress on the prognosis in COPD patients (2012)
  • Author(s): Nakayama K, et al
  • Organizer: American Thoracic Society 2012 International Conference.
  • Place of Presentation: San Francisco, USA
• [Book] Annual Review呼吸器2013 (2013)
  • Author(s): 中山勝敏
  • Total Pages: 292
  • Publisher: 中外医学社