九州大学 研究者情報
論文一覧
松元 幸一郎(まつもと こういちろう) データ更新日:2021.05.20

准教授 /  医学研究院 附属胸部疾患研究施設 九州大学大学院医学研究院附属胸部疾患研究施設


原著論文
1. Yamamoto N, Kan-o K, Tatsuta M, Ishii Y, Ogawa T, Shinozaki S, Fukuyama S, Nakanishi Y, Matsumoto K., Incense smoke-induced oxidative stress disrupts tight junctions and bronchial epithelial barrier integrity and induces airway hyperresponsiveness in mouse lungs., Scientific Reports, 11, 7222, 11, 7222, 2021.03, 線香はアジアや中東の多くの国で、宗教的行事や香りを楽しむものとして慣習的に使用されています。線香を燃やすと多くの有害物質が発生し、タバコの燃焼時よりも高濃度のPM2.5が室内に長時間浮遊することが知られています。また最近の臨床研究で、線香を日常的に使用する家庭の子供は、使用しない家庭と比べて喘息のリスクが高く、肺機能も低下しやすくなることが報告されています。しかし、線香煙の吸入が、肺や気道の機能にどのように影響するのかは不明でした。本研究では、マウスに線香煙を吸入させると、気道過敏性が亢進(気道が収縮し喘息をおこしやすくなる)し、肺のタイトジャンクション蛋白の発現が低下することを明らかにしました。さらに、線香煙は気道を覆う上皮細胞のバリア機能を低下させました。タイトジャンクション蛋白は、細胞同士を密に結合させ気道上皮のバリア機能を保っており、炎症の原因となる吸入抗原が体内へ侵入することを防いでいます。これらの線香煙によるマウスの肺や気道への有害な作用は、線香煙吸入後に発生する酸化ストレスによるものであり、抗酸化剤を使用することで症状を改善することができます。.
2. Takeshita T, Matsumoto K, Furuta M, Fukuyama S, Takeuchi K, Ogata H, Asakawa M, Kageyama S, Hata J, Ninomiya T, Inoue H, Yamashita Y., Airflow limitation and tongue microbiota in community-dwelling elderly individuals., ERJ Open Research, DOI: 10.1183/23120541.00616.2020, DOI: 10.1183/23120541.00616.2020, 2021.02, 舌の表面の溝には大量の常在細菌が生息しており、ここから剥がれ落ちた細菌を我々は常時飲み込んでいます。これらの細菌の大部分は食道を通過して胃に運ばれほぼ死滅しますが、ごく微量ながら気道にも流入していることが最近明らかとなってきました。一方で唾液中の細菌の供給源となる舌の常在細菌叢の状態が気道や肺に与える影響はこれまで注目されてきませんでした。今回、研究グループでは福岡県久山町の70〜80歳の高齢者 484 名の舌苔細菌叢の状態と慢性閉塞性肺疾患(COPD)の特徴である気流制限の有無との関連を検討しました。その結果、舌上の総細菌量が多い者(上位50%)では少ない者(下位50%)に比べ気流制限の頻度が高いことが明らかとなりました。特に優占種の一つであるPrevotella melaninogenicaの量が多いほど気流制限の頻度が高い傾向が認められました。これらの結果は口腔管理による舌の常在細菌叢の制御が肺機能の維持に役立つ可能性を示しています。.
3. Yanagihara T, Tanaka K, Matsumoto K, A measuring method for occupancy of immune checkpoint inhibitors in the cell surface., Biochemical Biophysical Research Communications, 527, 213-217, 527, 213-217, 2020.05.
4. Suzuki K, Yanagihara T, Matsumoto K, Kusaba H, Yamauchi T, Ikematsu Y, Tanaka K, Otsubo K, Inoue H, Yoneshima Y, Iwama E, Arimura-Omori M, Harada E, Hamada N, Okamoto I, Nakanishi Y., Immune-checkpoint profiles for T cells in bronchoalveolar lavage fluid of patients with immune-checkpoint inhibitor-related interstitial lung disease., International Immunology, 32, 8, 547-557, 32, 8, 547-557, 2020.08.
5. Fujita A, Kan-o K, Tonai K, Yamamoto N, Ogawa T, Fukuyama S, Nakananishi Y, Matsumoto K. , Inhibition of PI3Kd enhances poly I:C-induced antiviral responses and inhibits replication of human metapneumovirus in murine lungs and human bronchial epithelial cells., Front Immunol
, 11: 432, 2020.03, PI3 キナーゼ(*1)δ(デルタ)阻害剤が気道や肺からウイルスを排除しやすくする仕組みを明らかにし、ウイルスの増殖を抑制することを示しました。気道ウイルス感染症は気管支喘息や慢性閉塞性肺疾患 (*2)の発作を誘発し、さらなる病気の進行や QOL の悪化を招きますが、手指衛生やマスク装着による予防以外の手立ては限られています。
気道にウイルスが感染し増殖する際に、2 本鎖 RNA が合成されます。細胞内センサーによる 2 本鎖 RNA 認識・シグナル伝達を介して、自然免疫が活性化されます。ウイルスに対する代表的な自然免疫としては、①共抑制分子 PD-L1 (*3)の発現と②インターフェロン(I 型と III 型)産生が知られています。感染細胞上の①PD-L1 によりウイルスを排除しようとする T 細胞の機能が減弱化し、感染が持続すると考えられています。一方で②インターフェロンは抗ウイルス応答を引き起こし、細胞からウイルスを排除します。また PI3 キナーゼは細胞内の様々な重要シグナル伝達を引き起こす酵素であり、そのうちの一つである PI3 キナーゼδの自然免疫への関与の有無は不明でした。本研究ではマウス肺とヒトから採取した気道上皮細胞を用いて、PI3 キナーゼδ阻害剤(IC87114)のウイルスに対する自然免疫への効果を解析した結果、PI3 キナーゼδ阻害剤は合成 2 本鎖 RNA による①PD-L1 の発現上昇を抑制し、②インターフェロンの産生を増強しました。さらに気道上皮細胞に感染したヒトメタニューモウイルス(*4)の増殖抑制効果を認めました。これらの結果より、PI3 キナーゼδ阻害剤は、気道ウイルス感染症の治療薬となりうることが期待されます。.
6. Tatsuta M, Kan-o K, Ishii Y, Yamamoto N, Ogawa T, Fukuyama S, Ogawa A, Fujita A, Nakanishi Y, Matsumoto K., Effects of cigarette smoke on barrier function and tight junction proteins in the bronchial epithelium: protective role of cathelicidin LL-37.

, Respir Res , 20, 1, 251, 20(1): 251, 2019., 2019.11.
7. Takeuchi K, Matsumoto K, Furuta M, Fukuyama S, Takeshita T, Ogata H, Suma S, Shibata Y, Shimazaki Y, Hata J, Ninomiya T, Nakanishi Y, Inoue H, Yamashita Y., Periodontitis is associated with chronic obstructive pulmonary disease.
, J Dent Res
, 98(5): 534-540, 2019.05, COPDは、慢性気管支炎や肺気腫と呼ばれてきた病気の総称で、WHOの報告では2016年に世界の死因の第3位となり、重要な社会問題となっています。COPD発症の要因は喫煙を主とする有害物質の長期吸入であることは知られていましたが、非喫煙者の発症要因はこれまで謎でした。
 今回、研究グループは近年全身の健康を脅かす病気として知られる歯周病に着目し、福岡県久山町の60歳以上成人900名の追跡調査データを分析し、COPD発症との関連を検討しました。その結果、喫煙などの影響を加味した上でも、歯茎が健康な人や歯周病が軽度の人に比べ、歯周病が重度な人はCOPDを5年以内に発症する割合が3.5倍も高く、COPD患者の約4人に1人は中等度以上の歯周病が原因である可能性が示されました。このことは、歯周病の予防のために普段から自宅や歯科医院で口内環境を健康に保つことはもちろん、歯周病になっても適切な歯周病治療を受けて重症化を未然に防ぐことで、COPD発症のリスクが下がる可能性を示しています。.
8. Ogata H, Hirakawa Y, Matsumoto K, Hata J, Yoshida D, Fukuyama S, Inoue H, Kitazono T, Ninomiya T, Nakanishi Y. , Trends in the prevalence of airflow limitation in a general Japanese population: two serial cross-sectional surveys from the Hisayama Study.
, BMJ Open, 9(3), e023673, 2019
, 9(3), e023673
, 2019.03.
9. Takeuchi K, Matsumoto K, Furuta M, Fukuyama S, Takeshita T, Ogata H, Suma S, Shibata Y, Shimazaki Y, Hata J, Ninomiya T, Nakanishi Y, Inoue H, Yamashita Y., Periodontal status and lung function decline in the community: the Hisayama study., Sci Rep, 8(1): 13354, 2018.01.
10. Ogata H, Matsumoto K, Nakatomi K, Nakashima N, Shoji F, Koto H. , Seasonal and meteorological impacts on primary spontaneous pneumothorax.
, J Thorac Dis
, 10: 3957-3964, 2018.10.
11. Tamura K, Matsumoto K, Fukuyama S, Kan-o K, Ishii Y, Tonai K, Tatsuta M, Enokizu A, Inoue H, Nakanishi Y., Frequency-dependent airway hyperresponsiveness in a mouse model of emphysema and allergic inflammation., Physiol Rep, 6(2): e13568, 2018.02.
12. Seki N, Kan-o K, Matsumoto K, Fukuyama S, Hamano S, Tonai K, Ota K, Inoue H, Nakanishi Y. , Interleukin-22 attenuates double-stranded RNA-induced upregulation of PD-L1 in airway epithelial cells via a STAT3-dependent mechanism. , Biochem Biophys Res Commun.

, 94, 242-248, 2017.10.
13. Kudo K, Hata J, Matsumoto K, Shundo Y, Fukuyama S, Inoue H, Kitazono T, Kiyohara Y, Ninomiya T, Nakanishi Y. , Association of Airflow Limitation with Carotid Atherosclerosis in a Japanese Community‐The Hisayama Study. , Circulation Journal, 81, 1846-1853, 2017.06.
14. Samukawa S, Matsumoto K, Tsukuya G, Koriyama C, Fukuyama S, Uchida A, Mizuno K, Miyahara H, Kiyohara Y, Ninomiya T, Inoue H. , Development a self-scored persistent airflow obstruction screening questionnaire (COPD-Q) in a general Japanese population: the Hisayama study. , Int J COPD
, 12, 1468-1481, 2017.06, BACKGROUND:
The use of a simple screening questionnaire to detect persistent airflow obstruction (AO) in COPD may facilitate the early, accurate diagnosis of COPD in general practice settings.

OBJECTIVE:
This study developed an original persistent AO questionnaire for screening individuals with COPD in a general Japanese population.

METHODS:
A working group was established to generate initial draft questionnaire items about COPD. Eligible subjects aged 40 and older living in Japan were solicited to participate in a health checkup from 2014 to 2015. In study I, 2,338 subjects who fully completed the initial draft questionnaire and who had valid spirometry measurements were statistically analyzed to determine the final questionnaire items as a COPD screening questionnaire (COPD-Q). Persistent AO was defined as a post-bronchodilator FEV1/FVC <0.70. In study II, the working group analyzed the weighted scores for individual items and established a cutoff point for the COPD-Q based on the data of 2,066 subjects in the Hisayama study. Receiver operating characteristic (ROC) curves were used to examine the ability of the COPD-Q to discriminate between subjects with and without AO.

RESULTS:
The five-item COPD-Q was established based on 19 initial draft items in study I and the weighted scores of individual items. The overall area under the ROC curve for the COPD-Q was 0.796 (95% confidence interval, 0.707-0.788). A cutoff of 4 points resulted in a sensitivity of 71.0% and a specificity of 70.1%. The positive predictive value was 10.8%, and the negative predictive value was 97.9%. The crude odds ratio of the COPD-Q for AO was 5.8.

CONCLUSION:
The five-item COPD-Q is a useful questionnaire for diagnosing persistent AO in a general Japanese population and is expected to be an effective first-stage screening tool for detecting COPD..
15. Hamano S, Matsumoto K, Tonai K, Fukuyama S, Kan-o K, Seki N, Inoue H, Nakanishi Y. , Effects of corticosteroid plus long-acting beta2-agonist on the expression of PD-L1 in double-stranded RNA-induced lung inflammation in mice. , J Inflammation.
, 14, 2, 2017.01.
16. Tsukuya G, Samukawa T, Matsumoto K, Fukuyama S, Kumamoto T, Uchida A, Koriyama C, Ninomiya T, Inoue H. , Comparison of the COPD Population Screener and International Primary Care Airway Group questionnaires in a general Japanese population: the Hisayama study. , Int J COPD
, 11, 1903-1909, 2016.06.
17. Fukuyama S, Matsumoto K, Kaneko Y, Kan-o K, Noda N, Tajiri Y, Nakano T, Ishii Y, Kiyohara Y, Nakanishi Y, Inoue H. , Prevalence of airflow limitation defined by pre- and post-bronchodilator spirometry in a community-based health checkup: the Hisayama Study. , Tohoku J Exp Med, 238, 179-184, 2016.06.
18. Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, Tanizaki J, Harada T, Matsumoto K, Takayama K, Takamori S, Kage M, Hoshino T, Nakanishi Y, Okamoto I., Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer., Clin Cancer Res, 21, 4014-4021, 2015.06.
19. Tsukuya G, Matsumoto K, Fukuyama S, Crawford B, Nakanishi Y, Ichinose M, Machda K, Samukawa T, Ninomiya T, Kiyohara Y, Inoue H, Validation of a COPD screening questionnaire and establishment of diagnostic cut-points in a Japanese general population: The Hisayama study., Allergology International, 64, 49-53, 2015.06.
20. Matsumoto K, Seki N, Fukuyama S, Moriwaki A, Kan-o K, Matsunaga Y, Noda N, Yoshida M, Koto H, Takata S, Nakanishi Y, Kiyohara Y, Inoue H, Prevalence of asthma with airflow limitation, COPD, and COPD with variable airflow limitation in older subjects in a general Japanese population. The Hisayama Study., Respiratory Investigation, 53, 22-29, 2015.06.
21. 松元 幸一郎, Yoichi Nakanishi, Okamoto I., Harada T, Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer., Clinical Cancer Research, 21, 4014-4021, 2015.08.
22. 松元 幸一郎, 福山 聡, Yoichi Nakanishi, Yutaka Kiyohara, 関七重, Prevalence of asthma with airflow limitation, COPD, and COPD with variable airflow limitation in older subjects in a general Japanese population. The Hisayama Study., 53, 22-29, 2015.01.
23. Keiko Kan-o, Koichiro Matsumoto, Yukari Asai-Tajiri, Saaka Hamano, Satoru FUKUYAMA, Nanae Seki, Yoichi Nakanishi, Hiromasa Inoue, PI3K-delta mediates double-stranded RNA-induced upregulation of B7-H1 in BEAS-2B airway epithelial cells., Biochemical and Biophysical Research Communications, 435, 195-201, 2013.05, Airway viral infection disturbs the health-related quality of life. B7-H1 (also known as PD-L1) is a coinhibitory molecule associated with the escape of viruses from the mucosal immunity, leading to persistent infection. Most respiratory viruses generate double-stranded (ds) RNA during replication. The stimulation of cultured airway epithelial cells with an analog of viral dsRNA, polyinosinic-polycytidylic acid (poly IC) upregulates the expression of B7-H1 via activation of the nuclear factor κB(NF-κB). The mechanism of upregulation was investigated in association with phosphatidylinositol 3-kinases (PI3Ks). Poly IC-induced upregulation of B7-H1 was profoundly suppressed by a pan-PI3K inhibitor and partially by an inhibitor or a small interfering (si)RNA for PI3Kδ in BEAS-2B cells. Similar results were observed in the respiratory syncytial virus-infected cells. The expression of p110δ was detected by Western blot and suppressed by pretreatment with PI3Kδ siRNA. The activation of PI3Kδ is typically induced by oxidative stress. The generation of reactive oxygen species was increased by poly IC. Poly IC-induced upregulation of B7-H1 was attenuated by N-acetyl-L-cysteine, an antioxidant, or by oxypurinol, an inhibitor of xanthine oxidase. Poly IC-induced activation of NF-κB was suppressed by a pan-PI3K inhibitor but not by a PI3Kδ inhibitor. These results suggest that PI3Kδ mediates dsRNA-induced upregulation of B7-H1 without affecting the activation of NF-κB..
24. Koichiro Matsumoto, Keiko Kan-o, Satoru FUKUYAMA, Hiromasa Inoue, Yoichi Nakanishi, Mast cells contribute to double-stranded RNA-induced augmentation of airway eosinophilia in a murine model of asthma, 14, 28, 2013.03, Background: Clinical studies showed the contribution of viral infection to the development of asthma. Although mast cells have multiple roles in the pathogenesis of allergic asthma, their role of in the virus-associated pathogenesis of asthma remains unknown. Most respiratory viruses generate double-stranded (ds) RNA during their replication. dsRNA provokes innate immune responses. We recently showed that an administration of polyinocinic polycytidilic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13.
Methods: The effect of poly IC on allergen-induced airway eosinophilia was investigated for mast cell-conserved Kit+/+ mice and -deficient KitW/KitW-v mice. The outcome of mast cell reconstitution was further investigated.
Results: Airway eosinophilia and IL-13 production were augmented by poly IC in Kit+/+ mice but not in KitW/KitW-v mice. When KitW/KitW-v mice were reconstituted with bone marrow-derived mast cells (BMMCs), the augmentation was restored. The augmentation was not induced in the mice systemically deficient for TIR domain-containing adaptor-inducing IFN- (TRIF) or interferon regulatory factor (IRF)-3, both mediate dsRNA-triggered innate immune responses. The augmentation was, however, restored in KitW/KitW-v mice reconstituted with TRIF-deficient or IRF-3-deficient BMMCs. Although leukotriene B4 and prostaglandin D2 are major lipid mediators released from activated mast cells, no their contribution was shown to the dsRNA-induced augmentation of airway eosinophilia.
Conclusions: We conclude that mast cells contribute to dsRNA-induced augmentation of allergic airway inflammation without requiring direct activation of mast cells with dsRNA or involvement of leukotriene B4 or prostaglandin D2.
.
25. Koichiro Matsumoto, Yukari Asai, Satoru Fukuyama, Keiko Kan-o, Yuko Matsunaga, Naotaka Noda, Hiroko Kitajima, Kentaro Tanaka, Yoichi Nakanishi, Hiromasa Inoue, IL-6 induced by double-stranded RNA augments allergic inflammation via suppression of Foxp3+T-cell/IL-10 axis, American Journal of Respiratory Cell and Molecular Biology, in press (Epub ahead of print), 2011.07, polycytidilic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13 from T cells (Matsumoto et al. AJRCMB 2011, 45: 31-39). However, a phenotype of asthma under severer load of dsRNA remains unknown.
D-galactosamine (D-GalN) is known as a strong sensitizer of poly IC. Mice were treated with poly IC plus D-GalN during allergen sensitization. A sublethal dose of poly IC/D-GalN augmented airway eosinophilia and CD4+T-cell accumulation in the lungs but not airway hyperresponsiveness. The augmented inflammation was associated with decreased IL-10 in the bronchoalveolar lavage fluid and decreased Foxp3+regulatory T cells in the lungs. Serum IL-6 was prominently higher in the mice treated with poly IC/D-GalN than in that with poly IC alone or D-GalN alone. Poly IC/D-GalN failed to augment airway eosinophilia after anti-IL-10 receptor mAb treatment during allergen challenge. Finally, anti-IL-6 receptor mAb treatment before poly IC/D-GalN completely prevented the decrease of IL-10 and Foxp3+regulatory T cells and the augmentation of airway inflammation.
These results indicate that enhanced production of IL-6 by poly IC/D-GalN induces the augmentation of allergic inflammation via suppression of Foxp3+regulatory T cell/IL-10 axis. IL-6 may be a target for preventing asthma augmentation related to severe virus infection.
.
26. Matsumoto K, Kan-O K, Eguchi-Tsuda M, Fukuyama S, Asai Y, Matsumoto T, Moriwaki A, Matsunaga Y, Tsutsui H, Kawai T, Takeuchi O, Akira S, Yagita H, Azuma M, Nakanishi Y, and Inoue H., Essential role of B7-H1 in double-stranded RNA-induced augmentation of an asthma phenotype in mice. , Am J Respir Cell Mol Biol., in press, 2011.06.
27. Koichiro Matsumoto, Hiromasa Inoue, Satoru Fukuyama, Miyuki Eguchi-Tsuda, Takafumi Matsumoto, Atsushi Moriwaki, Takako Nakano, Yoichi Nakanishi, Frequency of Foxp3+CD4+CD25+T cells associates with the phenotypes of allergic asthma, Respirology, 14, 187-194, 2009.05.
28. Inoue H, Komori M, Matsumoto T, Fukuyama S, Matsumura M, Nakano T, Tsuda M, Matsumoto K, Nanaya A, Moriwaki A, Aizawa H, Yoshida M, NakanIshi Y, Effect of salmeterol in patients with persistent asthma receiving inhaled corticosteroid plus theophylline, Respiration, Epub ahead of print, 2006.09.
29. Nakano T, Inoue H, Fukuyama S, Matsumoto K, Matsumura M, Tsuda M, Matsumoto T, Aizawa H, Nakanishi Y, Niflumic acid suppresses interleukin-13-induced asthma phenotypes, American Journal of Respiratory and Critical Care Medicine, 173:1216-1221, 2006.06.
30. Matsumoto K, Aizawa H, Inoue R, Hamano S, Ikeda S, Xie Z, Hirata M, Hara N, Ito Y, Effects of epithelial cell supernatant on membrane potential and contraction of dog airway smooth muscles., Am J Respir Cell Mol Biol, 10, 3, 322-330, 10: 322-330, 1994.04.
31. Aizawa H, Inoue H, Shigyo M, Takata S, Koto H, Matsumoto K, Hara N, VIP antagonists enhance exitatory cholinergic neurotransmission in the human airway., Lung, 172, 3, 159-167, 172: 159-167, 1994.01.
32. 相沢久道、高田昇平、執行睦実、松元幸一郎、井上博雅、原信之, 抑制性非アドレナリン非コリン作動性神経とNO., 日本胸部疾患学会雑誌, 33 : 174-178, 1995.01.

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