Detection of specific antigens from lung microbiome causing a dysfunction of airway mucociliary transport and its regulation of those signaling in chronic inflammatory airway diseases

• Project/Area Number: 15K09207
• 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: Tohoku University
• Principal Investigator: Tamada Tsutomu 東北大学, 大学病院, 講師 (80396473)
• Co-Investigator(Kenkyū-buntansha): 村松 聡士 東北大学, 医学系研究科, 大学院非常勤講師 (30732549) ; 奈良 正之 東北大学, 大学病院, 特任教授 (70374999)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 気道分泌 / 微生物叢 / Toll様受容体 / COPD増悪 / 重症喘息 / 過分泌 / 気道粘膜下腺 / パッチクランプ / 難治性喘息

Outline of Final Research Achievements

Little is known about the impact of innate immunity including Toll-like receptors (TLRs) on airway secretion. Here, we investigated whether TLR7 has a significant effect on physiological airway secretion from tracheal submucosal glands(SMG). Patch-clamp analyses revealed that TLR7 ligand inhibited the ACh-induced ionic currents. Intracellular calcium assays revealed that TLR7 attenuated the transient rises in the intracellular Ca2+ concentration ([Ca2+]i). Immunofluorescent staining revealed that TLR7 was co-localized with SERCA2. TLR7 expression was downregulated in COPD airways. These findings suggest that an activation of TLR7 accelerates the SERCA2-induced Ca2+ clearance, and that both a dysfunction of TLR7 and hyperactivation of TLR4/5 act together to cause prolonged airway hypersecretion. Improvement of TLR7 dysfunction could be a novel treatment for reducing the risk of exacerbations of COPD by controlling airway secretion.

Research Products

• [Journal Article] Risk factors for stomatitis in patients with lymphangioleiomyomatosis during treatment with sirolimus: A multicenter investigator-initiated prospective study. (2017)
  • Author(s): Kitamura N, Seyama K, Inoue Y, Nagai K, Suzuki M, Moriyama H, Takada T, Tazawa R, Hirai T, Mishima M, Hayashida M, Hirose M, Arai T, Sugimoto C, Hattori N, Watanabe K, Tamada T, Akazawa K, Tanaka T, Nakata K.
  • Journal Title: Pharmacoepidemiol Drug Saf. Volume: 26 Issue: 10 Pages: 1182-1189
  • DOI: 10.1002/pds.4259
  • Peer Reviewed / Open Access
• [Journal Article] Production of reactive persulfide species in chronic obstructive pulmonary disease (2017)
  • Author(s): Numakura T, Sugiura H, Akaike T, Ida T, Fujii S, Koarai A, Yamada M, Onodera K, Hashimoto Y, Tanaka R, Sato K, Shishikura Y, Hirano T, Yanagisawa S, Fujino N, Okazaki T, Tamada T, Hoshikawa Y, Okada Y, Ichinose M
  • Journal Title: Thorax Volume: 72 Issue: 12 Pages: 1074-1083
  • DOI: 10.1136/thoraxjnl-2016-209359
  • Peer Reviewed / Open Access
• [Journal Article] Decrease in an anti-ageing factor, growth differentiation factor 11, in chronic obstructive pulmonary disease. (2017)
  • Author(s): Onodera K, Sugiura H, Yamada M, Koarai A, Fujino N, Yanagisawa S, Tanaka R, Numakura T, Togo S, Sato K, Kyogoku Y, Hashimoto Y, Okazaki T, Tamada T, Kobayashi S, Yanai M, Miura M, Hoshikawa Y, Okada Y, Suzuki S, Ichinose M.
  • Journal Title: Thorax Volume: 2017 Issue: 10 Pages: 893-904
  • DOI: 10.1136/thoraxjnl-2016-209352
  • Peer Reviewed / Open Access
• [Journal Article] 特集COPDと喘息の最新治療 「COPDと喘息の病態生理」 (2017)
  • Author(s): 玉田 勉、一ノ瀬正和
  • Journal Title: 臨牀と研究 Volume: 94 Pages: 5-10
• [Journal Article] 特集 「喘息と COPDのオーバラップ症候群― 病態と治療」 ACOSの疾患概念 (2017)
  • Author(s): 玉田 勉、 一ノ瀬正和
  • Journal Title: アレルギーの臨床 Volume: 37 Pages: 17-21
• [Journal Article] Leukotriene Receptor Antagonists and Antiallergy Drugs. (2017)
  • Author(s): Tamada T, Ichinose M.
  • Journal Title: Handb Exp Pharmacol. Volume: 237 Pages: 153-169
  • DOI: 10.1007/164_2016_72
  • ISBN: 9783319521732, 9783319521756
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Coexisting COPD in elderly asthma with fixed airflow limitation: assessment by DLco %predicted and HRCT. (2017)
  • Author(s): Tamada T, Sugiura H, Takahashi T, Matsunaga K, Kimura K, Katsumata U, Ohta K, Ichinose M.
  • Journal Title: J Asthma Volume: 印刷中 Issue: 6 Pages: 1-9
  • DOI: 10.1080/02770903.2016.1247168
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lymphocyte Kv1.3-Channels in the Pathogenesis of Chronic Obstructive Pulmonary Disease: Novel Therapeutic Implications of Targeting the Channels by Commonly Used Drugs (2016)
  • Author(s): Kazama I, Tamada T.
  • Journal Title: Allergy Asthma Clin Immunol. Volume: 29 Issue: 1 Pages: 60-60
  • DOI: 10.1186/s13223-016-0168-3
  • Peer Reviewed / Open Access
• [Journal Article] itreous lavage fluid and bronchoalveolar lavage fluid have equal diagnostic value in sarcoidosis. (2016)
  • Author(s): Maruyama K, Inaba T, Tamada T, Kunikata H, Nakazawa T.
  • Journal Title: Medicine (Baltimore) Volume: 95 Issue: 49 Pages: e5531-e5531
  • DOI: 10.1097/md.0000000000005531
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and Safety of Long-Term Sirolimus Therapy for Asian Patients with Lymphangioleiomyomatosis (2016)
  • Author(s): Takada T, Mikami A, Kitamura N, Seyama K, Inoue Y, Nagai K, Suzuki M, Moriyama H, Akasaka K, Tazawa R, Hirai T, Mishima M, Hayashida M, Hirose M, Sugimoto C, Arai T, Hattori N, Watanabe K, Tamada T, Yoshizawa H, Akazawa K, Tanaka T, Yagi K, Young LR, McCormack FX, Nakata K
  • Journal Title: AnnalsATS Volume: 13 Issue: 11 Pages: 1912-1922
  • DOI: 10.1513/annalsats.201605-335oc
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 27-hydroxycholesterol accelerates cellular senescence in human lung resident cells. (2016)
  • Author(s): Hashimoto Y, Sugiura H, Togo S, Koarai A, Abe K, Yamada M, Ichikawa T, Kikuchi T, Numakura T, Onodera K, Tanaka R, Sato K, Yanagisawa S, Okazaki T, Tamada T, Kikuchi T, Hoshikawa Y, Okada Y, Ichinose M.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 310 Issue: 11 Pages: L1028-L1041
  • DOI: 10.1152/ajplung.00351.2015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Simultaneous development of sarcoidosis and cutaneous vasculitis in a patient with refractory Crohn's disease during infliximab therapy. (2016)
  • Author(s): Numakura T, Tamada T, Nara M, Muramatsu S, Murakami K, Kikuchi T, Kobayashi M, Muroi M, Okazaki T, Takagi S, Eishi Y, Ichinose M.
  • Journal Title: BMC Pulm Med. Volume: 16 Issue: 1 Pages: 30-30
  • DOI: 10.1186/s12890-016-0193-5
  • Peer Reviewed / Open Access
• [Journal Article] A Case of Acute Sarcoidosis with Fever and Polyarthralgia (2016)
  • Author(s): 小野寺克洋、玉田 勉、村松聡士、村上康司、奈良正之、小松理世、小林 誠、山田充啓、杉浦久敏、一ノ瀬正和
  • Journal Title: Nihon Naika Gakkai Zasshi Volume: 105 Issue: 3 Pages: 540-546
  • DOI: 10.2169/naika.105.540
  • NAID: 130005439474
  • ISSN: 0021-5384, 1883-2083
  • Peer Reviewed / Open Access
• [Journal Article] 喘息における長時間作用性吸入抗コリン薬 (2016)
  • Author(s): 玉田 勉
  • Journal Title: アレルギーの臨床 Volume: 36 Pages: 22-26
• [Journal Article] 閉塞性肺疾患（SASを含む） (2016)
  • Author(s): 玉田 勉
  • Journal Title: EBM 呼吸器疾患の治療 Volume: 1 Pages: 31-36
• [Journal Article] ACOSを巡る新しい話題 (2016)
  • Author(s): 玉田 勉、一ノ瀬正和
  • Journal Title: Annual Review 2016 呼吸器 Volume: 1 Pages: 137-144
• [Journal Article] Toll様受容体システムの気道分泌への関与 (2016)
  • Author(s): 玉田 勉
  • Journal Title: アレルギーの臨床 Volume: 26 Pages: 45-51
• [Journal Article] Possible role of Krüppel-like factor 5 in the remodeling of small airways and pulmonary vessels in chronic obstructive pulmonary disease. (2016)
  • Author(s): Abe. K., H. Sugiura, Y. Hashimoto, T. Ichikawa, A. Koarai, M. Yamada, T. Numakura, K. Onodera, R. Tanaka, K. Sato, S. Yanagisawa, T. Okazaki, T. Tamada, T. Kikuchi and M. Ichinose.
  • Journal Title: Respir Res Volume: 17 Issue: 1 Pages: 7-7
  • DOI: 10.1186/s12931-016-0322-y
  • Peer Reviewed / Open Access
• [Journal Article] Biomarker-based detection of ACOS in COPD populations. (2015)
  • Author(s): Tamada, T., H. Sugiura, T. Takahashi, K. Matsunaga, K. Kimura, U. Katsumata, D. Takekoshi, T. Kikuchi, K. Ohta and M. Ichinose.
  • Journal Title: Int J Chron Obstruct Pulmon Di Volume: 10 Pages: 2169-2176
  • DOI: 10.2147/copd.s88274
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 喘息予防・管理ガイドライン2015改訂のポイントと今後の展望 3-1) 気道炎症の評価 (2015)
  • Author(s): 玉田 勉
  • Journal Title: Progress in Medicine Volume: 35 Pages: 1541-1547
• [Journal Article] 呼吸器疾患の新治療「スピオルト・レスピマット」 (2015)
  • Author(s): 玉田 勉、一ノ瀬正和
  • Journal Title: 呼吸 Volume: 35 Pages: 994-1003
• [Journal Article] アレルギー疾患のフェノタイプとエンドタイプ 『COPDを合併する喘息の病態と治療』 (2015)
  • Author(s): 玉田 勉、一ノ瀬正和
  • Journal Title: アレルギー・免疫 Volume: 22 Pages: 60-71
• [Journal Article] 呼吸器疾患の新治療「アノーロ」 (2015)
  • Author(s): 玉田 勉、一ノ瀬正和
  • Journal Title: 呼吸 Volume: 34 Pages: 491-500
• [Journal Article] 解説 COPDとのオーバーラップ：Asthma COPD overlap syndrome（ACOS） (2015)
  • Author(s): 玉田 勉、一ノ瀬正和
  • Journal Title: 呼吸器内科 Volume: 27 Pages: 228-235
• [Journal Article] 気管・気管支軟化症 (2015)
  • Author(s): 奈良正之、玉田 勉
  • Journal Title: 呼吸 Volume: 33 Pages: 304-308
• [Journal Article] 気管支喘息の気道炎症を反映するバイオマーカー (2015)
  • Author(s): 玉田 勉、一ノ瀬正和
  • Journal Title: 内科 アレルギー・免疫 Volume: 22 Pages: 28-37
• [Presentation] Upregulation of Ca2+-ATPase by TLR7 Decreases Electrolyte Secretion from Airway Submucosal Gland Cells (2017)
  • Author(s): Gamo S, Tamada T, Murakami K, Muramatsu S, Aritake H, Nara M, Kazama I, Sugiura H, Ichinose M.
  • Organizer: 2017 ATS International Conference in Washington DC
  • Int'l Joint Research
• [Presentation] 客観的指標を用いたCOPD合併喘息の検討 (2017)
  • Author(s): 玉田 勉、杉浦 久敏、高橋 識至、松永 和人、勝又 宇一郎、木村 啓二、大田 健、一ノ瀬 正和
  • Organizer: 第51回 東北アレルギー懇話会
• [Presentation] TLR7リガンドによる気道分泌抑制作用の細胞内機序について (2017)
  • Author(s): 蒲生俊一、玉田 勉、村上康司、村松聡士、有竹秀美 、奈良正之、風間逸郎 、杉浦久敏、一ノ瀬正和
  • Organizer: 第57回日本呼吸器学会学術講演会
• [Presentation] 客観的指標を用いたCOPD合併喘息の検討 (2017)
  • Author(s): 玉田 勉、杉浦 久敏、高橋 識至、松永 和人、勝又 宇一郎、木村 啓二、大田 健、一ノ瀬 正和
  • Organizer: 第57回日本呼吸器学会学術講演会
• [Presentation] Comorbidity in asthma (2017)
  • Author(s): Tsutomu Tamada
  • Organizer: The 6th Conference of International Union Against Tuberculosis and Lung Disease Asia Pacific Region, 2017
  • Place of Presentation: Tokyo, Tokyo International Forum
  • Int'l Joint Research / Invited
• [Presentation] Ｔoll like receptor 7 regulates the electrolytes secretion from airway submucosal gland. (2016)
  • Author(s): Gamo S, Muramatsu S, Murakami K, Tamada T, Nara M, Sugiura H, Ichinose M.
  • Organizer: 2016 ATS International Conference
  • Place of Presentation: San Francisco, USA
  • Int'l Joint Research
• [Presentation] 当院科外来で全身性サルコイドーシスのフォロー中、寛解後に増悪を認めた症例の臨床的検討 (2016)
  • Author(s): 蒲生俊一、玉田 勉、村松聡士、村上康司、奈良正之、杉浦久敏、一ノ瀬正和
  • Organizer: 第36回日本サルコイドーシス/肉芽腫性疾患学会総会
  • Place of Presentation: 東京、東京医科歯科大学 M＆Dタワー2階 鈴木章夫記念講堂
• [Presentation] 組織学的に診断された卵管サルコイドーシスの1例 (2016)
  • Author(s): 村松聡士、玉田 勉、奈良正之、村上康司、蒲生俊一、丸山和一、久野貴司、立花眞仁、杉浦久敏、八重樫伸生、一ノ瀬正和
  • Organizer: 第36回日本サルコイドーシス/肉芽腫性疾患学会総会
  • Place of Presentation: 東京、東京医科歯科大学 M＆Dタワー2階 鈴木章夫記念講堂
• [Presentation] バイオマーカーに基づく喘息-COPDオーバーラップ症候群の検出 (2016)
  • Author(s): 玉田 勉、杉浦久敏、高橋識至、松永和人、勝又宇一郎、木村啓二、大田 健、一ノ瀬正和
  • Organizer: 第56回日本呼吸器学会学術講演会
  • Place of Presentation: 京都、国立京都国際会館
• [Presentation] TLR7の気道粘膜下腺細胞での発現と分泌機能への影響 (2016)
  • Author(s): 蒲生俊一、玉田 勉、村松聡士、奈良正之、村上康司、杉浦久敏、一ノ瀬正和
  • Organizer: 第56回日本呼吸器学会学術講演会
  • Place of Presentation: 京都、国立京都国際会館
• [Presentation] メタボロミクス解析を用いたサルコイドーシス新規バイオマーカーの検索 (2016)
  • Author(s): 村松聡士, 玉田 勉, 三枝大輔, 奈良正之, 蒲生俊一, 村上康司, 杉浦久敏, 一ノ瀬正和
  • Organizer: 第56回日本呼吸器学会学術講演会
  • Place of Presentation: 京都、国立京都国際会館
• [Presentation] 最近のCOPD治療薬に期待する効果とそのエビデンス (2015)
  • Author(s): 玉田 勉
  • Organizer: 第85回日本呼吸器学会近畿地方会 ランチョンセミナー①
  • Place of Presentation: 奈良県文化会館（奈良市）
  • Year and Date: 2015-07-11
• [Presentation] Effects of TLR ligands on the intracellular calcium signaling in tracheal submucosal gland acinar cells. (2015)
  • Author(s): Muramatsu, S., T. Tamada, M. Nara, S. Gamow, K. Murakami, T. Kikuchi and M. Ichinose.
  • Organizer: ATS 2015 International Conference
  • Place of Presentation: Denver, CO, USA
  • Year and Date: 2015-05-16
  • Int'l Joint Research
• [Presentation] 気道分泌調整因子としてのTLRリガンドの細胞内カルシウム濃度への影響 (2015)
  • Author(s): 蒲生俊一、玉田 勉、村松聡士、村上康司、奈良正之、菊地利明、一ノ瀬正和
  • Organizer: 第55回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都）
  • Year and Date: 2015-04-19
• [Presentation] 診断基準改訂前後の当科におけるサルコイドーシスと悪性腫瘍の合併例の検討 (2015)
  • Author(s): 村松聡士、玉田 勉、奈良正之、村上康司、蒲生俊一、菊地利明、一ノ瀬正和
  • Organizer: 第55回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都）
  • Year and Date: 2015-04-18
• [Presentation] 東北大学病院呼吸器バイオバンクの現状と課題 (2015)
  • Author(s): 宮内栄作、光石陽一郎、東出直樹、椎原淳、三橋善哉、村松聡士、小林誠、佐藤輝幸、玉井ときわ、山田充啓、小荒井晃、井上彰、岡崎達馬、大河内眞也、玉田 勉、杉浦久敏、一ノ瀬正和
  • Organizer: 第55回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都）
  • Year and Date: 2015-04-17