研究者詳細 - 阪本　考司

Fibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis 国際共著国際誌

Nakahara, Y; Hashimoto, N; Sakamoto, K; Enomoto, A; Adams, TS; Yokoi, T; Omote, N; Poli, S; Ando, A; Wakahara, K; Suzuki, A; Inoue, M; Hara, A; Mizutani, Y; Imaizumi, K; Kawabe, T; Rosas, IO; Takahashi, M; Kaminski, N; Hasegawa, Y

EUROPEAN RESPIRATORY JOURNAL 58 巻 ( 6 ) 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：European Respiratory Journal

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine of the pathogenesis of IPF, identification of functional fibroblasts is warranted. This study was aimed to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis. We characterized meflin-positive cells in a single cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243,472 cells from 32 IPF lungs and 29 normal lung samples. scRNA-seq combined with in situ RNA hybridization identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic property to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution. These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.

DOI： 10.1183/13993003.03397-2020

Inhalation adherence for asthma and COPD improved during the COVID-19 pandemic: a questionnaire survey at a university hospital in Japan 国際誌

Serum mitochondrial DNA predicts the risk of acute exacerbation and progression of idiopathic pulmonary fibrosis 査読有り国際共著国際誌

Sakamoto Koji, Furukawa Taiki, Yamano Yasuhiko, Kataoka Kensuke, Teramachi Ryo, Walia Anjali, Suzuki Atsushi, Inoue Masahide, Nakahara Yoshio, Ryu Changwan, Hashimoto Naozumi, Kondoh Yasuhiro

EUROPEAN RESPIRATORY JOURNAL 57 巻 ( 1 ) 2021年1月

Prognostic Impact and Risk Factors of Immune-Related Pneumonitis in Patients With Non-Small-Cell Lung Cancer Who Received Programmed Death 1 Inhibitors 査読有り国際誌

Fukihara Jun, Sakamoto Koji, Koyama Junji, Ito Takayasu, Iwano Shingo, Morise Masahiro, Ogawa Masahiro, Kondoh Yasuhiro, Kimura Tomoki, Hashimoto Naozumi, Hasegawa Yoshinori

CLINICAL LUNG CANCER 20 巻 ( 6 ) 頁： 442 - + 2019年11月

Mild elevation of pulmonary vascular resistance predicts mortality regardless of mean pulmonary artery pressure in mild interstitial lung disease. 査読有り

Sato T, Furukawa T, Teramachi R, Fukihara J, Yamano Y, Yokoyama T, Matsuda T, Kataoka K, Kimura T, Sakamoto K, Ishii M, Kondoh Y.

Thorax 2024年2月

ect Kato S, Sakamoto K, Sato T, Kobayashi T, Shindo Y, Morise M, Iwama S, Arima H, Ishii M. Rapidly progressive interstitial lung disease with positive anti-MDA5 antibody as an immune-related complication of nivolumab: A case report. 査読有り

Kato S, Sakamoto K, Sato T, Kobayashi T, Shindo Y, Morise M, Iwama S, Arima H, Ishii M.

Respiratory Investigation 62 巻 ( 2 ) 頁： 313 - 316 2024年2月

Cohort study to evaluate prognostic factors in idiopathic pulmonary fibrosis patients introduced to oxygen therapy. 査読有り

Kataoka K, Oda K, Takizawa H, Ogura T, Miyamoto A, Inoue Y, Akagawa S, Hashimoto S, Kishaba T, Sakamoto K, Hamada N, Kuwano K, Nakayama M, Ebina M, Enomoto N, Miyazaki Y, Atsumi K, Izumi S, Tanino Y, Ishii H, Ohnishi H, Suda T, Kondoh Y.

Scientific Reports 13 巻 ( 1 ) 頁： 13664 2023年8月

Fukutani Eriko, Wakahara Keiko, Nakamura Saya, Yokoi Eito, Yoshimi Akira, Miyazaki Masayuki, Nakamura Mariko, Shindo Yuichiro, Sakamoto Koji, Okachi Shotaro, Tanaka Ichidai, Hamajima Nobuyuki, Noda Yukihiro, Hashimoto Naozumi, Ishii Makoto

JOURNAL OF ASTHMA 頁： 1 - 12 2023年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Asthma

Background: Good adherence to an inhaled medication protocol is necessary for the management of asthma and chronic obstructive pulmonary disease (COPD), and several interventions to improve adherence have been reported. However, the impact of patient life changes and psychological aspects on treatment motivation is obscure. Here, we investigated changes in inhaler adherence during the COVID-19 pandemic and how lifestyle and psychological changes affected it. Methods: Seven-hundred sixteen adult patients with asthma and COPD who had visited Nagoya University Hospital between 2015 and 2020 were selected. Among them, 311 patients had received instruction at a pharmacist-managed clinic (PMC). We distributed one-time cross-sectional questionnaires from January 12 to March 31, 2021. The questionnaire covered the status of hospital visits, inhalation adherence before and during the COVID-19 pandemic, lifestyles, medical conditions, and psychological stress. The Adherence Starts with Knowledge-12 (ASK-12) was used to assess adherence barriers. Results: Four-hundred thirty-three patients answered the questionnaire. Inhalation adherence was significantly improved in both diseases during the COVID-19 pandemic. The most common reason for improved adherence was fear of infection. Patients with improved adherence were more likely to believe that controller inhalers could prevent COVID-19 from becoming more severe. Improved adherence was more common in patients with asthma, those not receiving counseling at PMC, and those with poor baseline adherence. Conclusions: Inhalation adherence for asthma and COPD improved in the COVID-19 pandemic. The patients seemed to realize the necessity and benefits of the medication more strongly than before the pandemic, which motivated them to improve adherence.

DOI： 10.1080/02770903.2023.2209173

Acute exacerbation of rheumatoid arthritis-associated interstitial lung disease triggered by COVID-19: What is the best practice for treatment? 査読有り

Yonezawa T, Suzuki A, Fukumitsu K, Katano T, Kako H, Ishii M, Niimi A, Imaizumi K, Sakamoto K, Omote N, Yamaguchi E.

Respiratory Medicine Case Report 43 巻頁： 101857 2023年4月

Long-term effect of pulmonary rehabilitation in idiopathic pulmonary fibrosis: a randomised controlled trial. 査読有り国際誌

Kataoka K, Nishiyama O, Ogura T, Mori Y, Kozu R, Arizono S, Tsuda T, Tomioka H, Tomii K, Sakamoto K, Ishimoto H, Kagajo M, Ito H, Ichikado K, Sasano H, Eda S, Arita M, Goto Y, Hataji O, Fuke S, Shintani R, Hasegawa H, Ando M, Ogawa T, Shiraishi M, Watanabe F, Nishimura K, Sasaki T, Miyazaki S, Saka H, Kondoh Y, FITNESS study Collaborators

Thorax 78 巻 ( 8 ) 頁： 784 - 791 2023年4月

<i>DOCK2</i> is involved in the host genetics and biology of severe COVID-19 国際誌

Namkoong, H; Edahiro, R; Takano, T; Nishihara, H; Shirai, Y; Sonehara, K; Tanaka, H; Azekawa, S; Mikami, Y; Lee, H; Hasegawa, T; Okudela, K; Okuzaki, D; Motooka, D; Kanai, M; Naito, T; Yamamoto, K; Wang, QBS; Saiki, R; Ishihara, R; Matsubara, Y; Hamamoto, J; Hayashi, H; Yoshimura, Y; Tachikawa, N; Yanagita, E; Hyugaji, T; Shimizu, E; Katayama, K; Kato, Y; Morita, T; Takahashi, K; Harada, N; Naito, T; Hiki, M; Matsushita, Y; Takagi, H; Aoki, R; Nakamura, A; Harada, S; Sasano, H; Kabata, H; Masaki, K; Kamata, H; Ikemura, S; Chubachi, S; Okamori, S; Terai, H; Morita, A; Asakura, T; Sasaki, J; Morisaki, H; Uwamino, Y; Nanki, K; Uchida, S; Uno, S; Nishimura, T; Ishiguro, T; Isono, T; Shibata, S; Matsui, Y; Hosoda, C; Takano, K; Nishida, T; Kobayashi, Y; Takaku, Y; Takayanagi, N; Ueda, S; Tada, A; Miyawaki, M; Yamamoto, M; Yoshida, E; Hayashi, R; Nagasaka, T; Arai, S; Kaneko, Y; Sasaki, K; Tagaya, E; Kawana, M; Arimura, K; Takahashi, K; Anzai, T; Ito, S; Endo, A; Uchimura, Y; Miyazaki, Y; Honda, T; Tateishi, T; Tohda, S; Ichimura, N; Sonobe, K; Sassa, CT; Nakajima, J; Nakano, Y; Nakajima, Y; Anan, R; Arai, R; Kurihara, Y; Harada, Y; Nishio, K; Ueda, T; Azuma, M; Saito, R; Sado, T; Miyazaki, Y; Sato, R; Haruta, Y; Nagasaki, T; Yasui, Y; Hasegawa, Y; Mutoh, Y; Kimura, T; Sato, T; Takei, R; Hagimoto, S; Noguchi, Y; Yamano, Y; Sasano, H; Ota, S; Nakamori, Y; Yoshiya, K; Saito, F; Yoshihara, T; Wada, D; Iwamura, H; Kanayama, S; Maruyama, S; Yoshiyama, T; Ohta, K; Kokuto, H; Ogata, H; Tanaka, Y; Arakawa, K; Shimoda, M; Osawa, T; Tateno, H; Hase, I; Yoshida, S; Suzuki, S; Kawada, M; Horinouchi, H; Saito, F; Mitamura, K; Hagihara, M; Ochi, J; Uchida, T; Baba, R; Arai, D; Ogura, T; Takahashi, H; Hagiwara, S; Nagao, G; Konishi, S; Nakachi, I; Murakami, K; Yamada, M; Sugiura, H; Sano, H; Matsumoto, S; Kimura, N; Ono, Y; Baba, H; Suzuki, Y; Nakayama, S; Masuzawa, K; Namba, S; Suzuki, K; Naito, Y; Liu, YC; Takuwa, A; Sugihara, F; Wing, JB; Sakakibara, S; Hizawa, N; Shiroyama, T; Miyawaki, S; Kawamura, Y; Nakayama, A; Matsuo, H; Maeda, Y; Nii, T; Noda, Y; Niitsu, T; Adachi, Y; Enomoto, T; Amiya, S; Hara, R; Yamaguchi, Y; Murakami, T; Kuge, T; Matsumoto, K; Yamamoto, Y; Yamamoto, M; Yoneda, M; Kishikawa, T; Yamada, S; Kawabata, S; Kijima, N; Takagaki, M; Sasa, N; Ueno, Y; Suzuki, M; Takemoto, N; Eguchi, H; Fukusumi, T; Imai, T; Fukushima, M; Kishima, H; Inohara, H; Tomono, K; Kato, K; Takahashi, M; Matsuda, F; Hirata, H; Takeda, Y; Koh, H; Manabe, T; Funatsu, Y; Ito, F; Fukui, T; Shinozuka, K; Kohashi, S; Miyazaki, M; Shoko, T; Kojima, M; Adachi, T; Ishikawa, M; Takahashi, K; Inoue, T; Hirano, T; Kobayashi, K; Takaoka, H; Watanabe, K; Miyazawa, N; Kimura, Y; Sado, R; Sugimoto, H; Kamiya, A; Kuwahara, N; Fujiwara, A; Matsunaga, T; Sato, Y; Okada, T; Hirai, Y; Kawashima, H; Narita, A; Niwa, K; Sekikawa, Y; Nishi, K; Nishitsuji, M; Tani, M; Suzuki, J; Nakatsumi, H; Ogura, T; Kitamura, H; Hagiwara, E; Murohashi, K; Okabayashi, H; Mochimaru, T; Nukaga, S; Satomi, R; Oyamada, Y; Mori, N; Baba, T; Fukui, Y; Odate, M; Mashimo, S; Makino, Y; Yagi, K; Hashiguchi, M; Kagyo, J; Shiomi, T; Fuke, S; Saito, H; Tsuchida, T; Fujitani, S; Takita, M; Morikawa, D; Yoshida, T; Izumo, T; Inomata, M; Kuse, N; Awano, N; Tone, M; Ito, A; Nakamura, Y; Hoshino, K; Maruyama, J; Ishikura, H; Takata, T; Odani, T; Amishima, M; Hattori, T; Shichinohe, Y; Kagaya, T; Kita, T; Ohta, K; Sakagami, S; Koshida, K; Hayashi, K; Shimizu, T; Kozu, Y; Hiranuma, H; Gon, Y; Izumi, N; Nagata, K; Ueda, K; Taki, R; Hanada, S; Kawamura, K; Ichikado, K; Nishiyama, K; Muranaka, H; Nakamura, K; Hashimoto, N; Wakahara, K; Sakamoto, K; Omote, N; Ando, A; Kodama, N; Kaneyama, Y; Maeda, S; Kuraki, T; Matsumoto, T; Yokote, K; Nakada, TA; Abe, R; Oshima, T; Shimada, T; Harada, M; Takahashi, T; Ono, H; Sakurai, T; Shibusawa, T; Kimizuka, Y; Kawana, A; Sano, T; Watanabe, C; Suematsu, R; Sageshima, H; Yoshifuji, A; Ito, K; Takahashi, S; Ishioka, K; Nakamura, M; Masuda, M; Wakabayashi, A; Watanabe, H; Ueda, S; Nishikawa, M; Chihara, Y; Takeuchi, M; Onoi, K; Shinozuka, J; Sueyoshi, A; Nagasaki, Y; Okamoto, M; Ishihara, S; Shimo, M; Tokunaga, Y; Kusaka, Y; Ohba, T; Isogai, S; Ogawa, A; Inoue, T; Fukuyama, S; Eriguchi, Y; Yonekawa, A; Kan-o, K; Matsumoto, K; Kanaoka, K; Ihara, S; Komuta, K; Inoue, Y; Chiba, S; Yamagata, K; Hiramatsu, Y; Kai, H; Asano, K; Oguma, T; Ito, Y; Hashimoto, S; Yamasaki, M; Kasamatsu, Y; Komase, Y; Hida, N; Tsuburai, T; Oyama, B; Takada, M; Kanda, H; Kitagawa, Y; Fukuta, T; Miyake, T; Yoshida, S; Ogura, S; Abe, S; Kono, Y; Togashi, Y; Takoi, H; Kikuchi, R; Ogawa, S; Ogata, T; Ishihara, S; Kanehiro, A; Ozaki, S; Fuchimoto, Y; Wada, S; Fujimoto, N; Nishiyama, K; Terashima, M; Beppu, S; Yoshida, K; Narumoto, O; Nagai, H; Ooshima, N; Motegi, M; Umeda, A; Miyagawa, K; Shimada, H; Endo, M; Ohira, Y; Watanabe, M; Inoue, S; Igarashi, A; Sato, M; Sagara, H; Tanaka, A; Ohta, S; Kimura, T; Shibata, Y; Tanino, Y; Nikaido, T; Minemura, H; Sato, Y; Yamada, Y; Hashino, T; Shinoki, M; Iwagoe, H; Takahashi, H; Fujii, K; Kishi, H; Kanai, M; Imamura, T; Yamashita, T; Yatomi, M; Maeno, T; Hayashi, S; Takahashi, M; Kuramochi, M; Kamimaki, I; Tominaga, Y; Ishii, T; Utsugi, M; Ono, A; Tanaka, T; Kashiwada, T; Fujita, K; Saito, Y; Seike, M; Watanabe, H; Matsuse, H; Kodaka, N; Nakano, C; Oshio, T; Hirouchi, T; Makino, S; Egi, M; Omae, Y; Nannya, Y; Ueno, T; Katayama, K; Ai, M; Fukui, Y; Kumanogoh, A; Sato, T; Hasegawa, N; Tokunaga, K; Ishii, M; Koike, R; Kitagawa, Y; Kimura, A; Imoto, S; Miyano, S; Ogawa, S; Kanai, T; Fukunaga, K; Okada, Y

NATURE 609 巻 ( 7928 ) 頁： 754 - + 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

DOI： 10.1038/s41586-022-05163-5

A comprehensible machine learning tool to differentially diagnose idiopathic pulmonary fibrosis from other chronic interstitial lung diseases

Furukawa, T; Oyama, S; Yokota, H; Kondoh, Y; Kataoka, K; Johkoh, T; Fukuoka, J; Hashimoto, N; Sakamoto, K; Shiratori, Y; Hasegawa, Y

RESPIROLOGY 27 巻 ( 9 ) 頁： 739 - 746 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Respirology

Background and objective: Idiopathic pulmonary fibrosis (IPF) has poor prognosis, and the multidisciplinary diagnostic agreement is low. Moreover, surgical lung biopsies pose comorbidity risks. Therefore, using data from non-invasive tests usually employed to assess interstitial lung diseases (ILDs), we aimed to develop an automated algorithm combining deep learning and machine learning that would be capable of detecting and differentiating IPF from other ILDs. Methods: We retrospectively analysed consecutive patients presenting with ILD between April 2007 and July 2017. Deep learning was used for semantic image segmentation of HRCT based on the corresponding labelled images. A diagnostic algorithm was then trained using the semantic results and non-invasive findings. Diagnostic accuracy was assessed using five-fold cross-validation. Results: In total, 646,800 HRCT images and the corresponding labelled images were acquired from 1068 patients with ILD, of whom 42.7% had IPF. The average segmentation accuracy was 96.1%. The machine learning algorithm had an average diagnostic accuracy of 83.6%, with high sensitivity, specificity and kappa coefficient values (80.7%, 85.8% and 0.665, respectively). Using Cox hazard analysis, IPF diagnosed using this algorithm was a significant prognostic factor (hazard ratio, 2.593; 95% CI, 2.069–3.250; p < 0.001). Diagnostic accuracy was good even in patients with usual interstitial pneumonia patterns on HRCT and those with surgical lung biopsies. Conclusion: Using data from non-invasive examinations, the combined deep learning and machine learning algorithm accurately, easily and quickly diagnosed IPF in a population with various ILDs.

DOI： 10.1111/resp.14310

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/resp.14310

CINS: Cell Interaction Network inference from Single cell expression data. 査読有り国際共著国際誌

Ye Yuan, Carlos Cosme Jr, Taylor Sterling Adams, Jonas Schupp, Koji Sakamoto, Nikos Xylourgidis, Matthew Ruffalo, Jiachen Li, Naftali Kaminski, Ziv Bar-Joseph

PLoS computational biology 18 巻 ( 9 ) 頁： e1010468 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Studies comparing single cell RNA-Seq (scRNA-Seq) data between conditions mainly focus on differences in the proportion of cell types or on differentially expressed genes. In many cases these differences are driven by changes in cell interactions which are challenging to infer without spatial information. To determine cell-cell interactions that differ between conditions we developed the Cell Interaction Network Inference (CINS) pipeline. CINS combines Bayesian network analysis with regression-based modeling to identify differential cell type interactions and the proteins that underlie them. We tested CINS on a disease case control and on an aging mouse dataset. In both cases CINS correctly identifies cell type interactions and the ligands involved in these interactions improving on prior methods suggested for cell interaction predictions. We performed additional mouse aging scRNA-Seq experiments which further support the interactions identified by CINS.

DOI： 10.1371/journal.pcbi.1010468

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force. 査読有り国際誌

Wang QS, Edahiro R, Namkoong H, Hasegawa T, Shirai Y, Sonehara K, Tanaka H, Lee H, Saiki R, Hyugaji T, Shimizu E, Katayama K, Kanai M, Naito T, Sasa N, Yamamoto K, Kato Y, Morita T, Takahashi K, Harada N, Naito T, Hiki M, Matsushita Y, Takagi H, Ichikawa M, Nakamura A, Harada S, Sandhu Y, Kabata H, Masaki K, Kamata H, Ikemura S, Chubachi S, Okamori S, Terai H, Morita A, Asakura T, Sasaki J, Morisaki H, Uwamino Y, Nanki K, Uchida S, Uno S, Nishimura T, Ishiguro T, Isono T, Shibata S, Matsui Y, Hosoda C, Takano K, Nishida T, Kobayashi Y, Takaku Y, Takayanagi N, Ueda S, Tada A, Miyawaki M, Yamamoto M, Yoshida E, Hayashi R, Nagasaka T, Arai S, Kaneko Y, Sasaki K, Tagaya E, Kawana M, Arimura K, Takahashi K, Anzai T, Ito S, Endo A, Uchimura Y, Miyazaki Y, Honda T, Tateishi T, Tohda S, Ichimura N, Sonobe K, Sassa CT, Nakajima J, Nakano Y, Nakajima Y, Anan R, Arai R, Kurihara Y, Harada Y, Nishio K, Ueda T, Azuma M, Saito R, Sado T, Miyazaki Y, Sato R, Haruta Y, Nagasaki T, Yasui Y, Hasegawa Y, Mutoh Y, Kimura T, Sato T, Takei R, Hagimoto S, Noguchi Y, Yamano Y, Sasano H, Ota S, Nakamori Y, Yoshiya K, Saito F, Yoshihara T, Wada D, Iwamura H, Kanayama S, Maruyama S, Yoshiyama T, Ohta K, Kokuto H, Ogata H, Tanaka Y, Arakawa K, Shimoda M, Osawa T, Tateno H, Hase I, Yoshida S, Suzuki S, Kawada M, Horinouchi H, Saito F, Mitamura K, Hagihara M, Ochi J, Uchida T, Baba R, Arai D, Ogura T, Takahashi H, Hagiwara S, Nagao G, Konishi S, Nakachi I, Murakami K, Yamada M, Sugiura H, Sano H, Matsumoto S, Kimura N, Ono Y, Baba H, Suzuki Y, Nakayama S, Masuzawa K, Namba S, Shiroyama T, Noda Y, Niitsu T, Adachi Y, Enomoto T, Amiya S, Hara R, Yamaguchi Y, Murakami T, Kuge T, Matsumoto K, Yamamoto Y, Yamamoto M, Yoneda M, Tomono K, Kato K, Hirata H, Takeda Y, Koh H, Manabe T, Funatsu Y, Ito F, Fukui T, Shinozuka K, Kohashi S, Miyazaki M, Shoko T, Kojima M, Adachi T, Ishikawa M, Takahashi K, Inoue T, Hirano T, Kobayashi K, Takaoka H, Watanabe K, Miyazawa N, Kimura Y, Sado R, Sugimoto H, Kamiya A, Kuwahara N, Fujiwara A, Matsunaga T, Sato Y, Okada T, Hirai Y, Kawashima H, Narita A, Niwa K, Sekikawa Y, Nishi K, Nishitsuji M, Tani M, Suzuki J, Nakatsumi H, Ogura T, Kitamura H, Hagiwara E, Murohashi K, Okabayashi H, Mochimaru T, Nukaga S, Satomi R, Oyamada Y, Mori N, Baba T, Fukui Y, Odate M, Mashimo S, Makino Y, Yagi K, Hashiguchi M, Kagyo J, Shiomi T, Fuke S, Saito H, Tsuchida T, Fujitani S, Takita M, Morikawa D, Yoshida T, Izumo T, Inomata M, Kuse N, Awano N, Tone M, Ito A, Nakamura Y, Hoshino K, Maruyama J, Ishikura H, Takata T, Odani T, Amishima M, Hattori T, Shichinohe Y, Kagaya T, Kita T, Ohta K, Sakagami S, Koshida K, Hayashi K, Shimizu T, Kozu Y, Hiranuma H, Gon Y, Izumi N, Nagata K, Ueda K, Taki R, Hanada S, Kawamura K, Ichikado K, Nishiyama K, Muranaka H, Nakamura K, Hashimoto N, Wakahara K, Koji S, Omote N, Ando A, Kodama N, Kaneyama Y, Maeda S, Kuraki T, Matsumoto T, Yokote K, Nakada TA, Abe R, Oshima T, Shimada T, Harada M, Takahashi T, Ono H, Sakurai T, Shibusawa T, Kimizuka Y, Kawana A, Sano T, Watanabe C, Suematsu R, Sageshima H, Yoshifuji A, Ito K, Takahashi S, Ishioka K, Nakamura M, Masuda M, Wakabayashi A, Watanabe H, Ueda S, Nishikawa M, Chihara Y, Takeuchi M, Onoi K, Shinozuka J, Sueyoshi A, Nagasaki Y, Okamoto M, Ishihara S, Shimo M, Tokunaga Y, Kusaka Y, Ohba T, Isogai S, Ogawa A, Inoue T, Fukuyama S, Eriguchi Y, Yonekawa A, Kan-O K, Matsumoto K, Kanaoka K, Ihara S, Komuta K, Inoue Y, Chiba S, Yamagata K, Hiramatsu Y, Kai H, Asano K, Oguma T, Ito Y, Hashimoto S, Yamasaki M, Kasamatsu Y, Komase Y, Hida N, Tsuburai T, Oyama B, Takada M, Kanda H, Kitagawa Y, Fukuta T, Miyake T, Yoshida S, Ogura S, Abe S, Kono Y, Togashi Y, Takoi H, Kikuchi R, Ogawa S, Ogata T, Ishihara S, Kanehiro A, Ozaki S, Fuchimoto Y, Wada S, Fujimoto N, Nishiyama K, Terashima M, Beppu S, Yoshida K, Narumoto O, Nagai H, Ooshima N, Motegi M, Umeda A, Miyagawa K, Shimada H, Endo M, Ohira Y, Watanabe M, Inoue S, Igarashi A, Sato M, Sagara H, Tanaka A, Ohta S, Kimura T, Shibata Y, Tanino Y, Nikaido T, Minemura H, Sato Y, Yamada Y, Hashino T, Shinoki M, Iwagoe H, Takahashi H, Fujii K, Kishi H, Kanai M, Imamura T, Yamashita T, Yatomi M, Maeno T, Hayashi S, Takahashi M, Kuramochi M, Kamimaki I, Tominaga Y, Ishii T, Utsugi M, Ono A, Tanaka T, Kashiwada T, Fujita K, Saito Y, Seike M, Watanabe H, Matsuse H, Kodaka N, Nakano C, Oshio T, Hirouchi T, Makino S, Egi M, Omae Y, Nannya Y, Ueno T, Takano T, Katayama K, Ai M, Kumanogoh A, Sato T, Hasegawa N, Tokunaga K, Ishii M, Koike R, Kitagawa Y, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K, Okada Y

Nature communications 13 巻 ( 1 ) 頁： 4830 - 4830 2022年8月

COVID-19-Triggered Acute Exacerbation of IPF, an Underdiagnosed Clinical Entity With Two-Peaked Respiratory Failure: A Case Report and Literature Review 査読有り国際誌

Goto Yosuke, Sakamoto Koji, Fukihara Jun, Suzuki Atsushi, Omote Norihito, Ando Akira, Shindo Yuichiro, Hashimoto Naozumi

FRONTIERS IN MEDICINE 9 巻頁： 815924 2022年2月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Medicine

Because severe coronavirus disease 2019 (COVID-19) affects the respiratory system and develops into respiratory failure, patients with pre-existing chronic lung disorders, such as idiopathic pulmonary fibrosis (IPF), are thought to be at high risk of death. Patients with IPF often suffer from a lethal complication, acute exacerbation (AE), a significant part of which is assumed to be triggered by respiratory viral infection. However, whether mild to moderate COVID-19 can trigger AE in patients with IPF remains unknown. This is the case report of a 60-year-old man with a 4-year history of IPF who successfully recovered from moderate COVID-19 but subsequently developed more severe respiratory failure, which was considered to be a COVID-19-triggered acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). It is important to be aware of the risk of AE-IPF after COVID-19 and to properly manage this deadly complication of IPF. Recent literature reporting cases with chronic interstitial lung diseases which developed respiratory failure by complications with COVID-19 is also reviewed and discussed.

DOI： 10.3389/fmed.2022.815924

肺線維症の病態に関連する2つの新規マーカー分子:メフリンとミトコンドリアDNA

阪本考司, 橋本直純, 中原義夫, 古川大記

呼吸器内科 41 巻 ( 2 ) 頁： 197 - 201 2022年2月

Overexpression of bone morphogenetic protein receptor type 2 suppresses transforming growth factor beta-induced profibrotic responses in lung fibroblasts 査読有り国際共著国際誌

Fukihara Jun, Maiolo Suzanne, Kovac Jessica, Sakamoto Koji, Wakahara Keiko, Hashimoto Naozumi, Reynolds Paul N.

EXPERIMENTAL LUNG RESEARCH 48 巻 ( 1 ) 頁： 35 - 51 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Experimental Lung Research

Purpose of the study: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. As the efficacy of currently available antifibrotics is limited, development of new therapies is warranted. Transforming growth factor (TGF)-β plays a central role in the pathogenesis of IPF through mechanisms such as promoting the production of extracellular matrix by fibroblasts. Conversely, bone morphogenetic proteins (BMPs) are known to be antifibrotic and may counterbalance TGF-β signaling via BMP receptor type 2 (BMPR2). However, little is known about the expression status of BMPR2 and its function in pulmonary fibrosis, and manipulation of BMPR2 expression has never been attempted. In this study, we aimed at evaluating the effectiveness of BMPR2 upregulation for modulating the imbalance of the TGF-β/BMP axis and reduce the profibrotic changes in lung fibroblasts. Materials and Methods: We investigated BMPR2 expression in pulmonary fibrosis and TGF-β/BMP signaling in lung fibroblasts. Then we evaluated the impact of BMPR2 upregulation using adenoviral transduction on TGF-β-induced Smad2/3 phosphorylation and fibronectin production in lung fibroblasts. Results: BMPR2 was distributed in airway epithelium and alveolar walls in rat lungs. BMPR2 expression was decreased in fibrotic lesions in the lungs of rats with bleomycin-induced pulmonary fibrosis and in human lung fibroblasts (HLFs) stimulated with TGF-β. Although Smad2/3 phosphorylation and fibronectin production were not suppressed solely by BMPs, phosphorylated Smad2/3 was decreased in BMPR2-transduced cells even without BMP stimulation. Fibronectin was decreased only when BMPR2-transduced HLFs were stimulated with BMP7 (but not BMP4). Similar results were also observed in IPF patient HLFs and rat lung fibroblasts. Conclusions: BMPR2 expression was reduced in fibrotic lungs and lung fibroblasts stimulated with TGF-β. BMPR2 transduction to lung fibroblasts reduced Smad2/3 phosphorylation, and reduced fibronectin production when treated with BMP7. Upregulation of BMPR2 may be a possible strategy for treating pulmonary fibrosis.

DOI： 10.1080/01902148.2021.2024301

Successful Treatment with High-dose Steroids for Acute Exacerbation of Idiopathic Pulmonary Fibrosis Triggered by COVID-19

Omote Norihito, Kanemitsu Yoshihiro, Inoue Takahiro, Yonezawa Toshiyuki, Ichihashi Takuji, Shindo Yuichiro, Sakamoto Koji, Ando Akira, Suzuki Atsushi, Niimi Akio, Ito Satoru, Imaizumi Kazuyoshi, Hashimoto Naozumi

INTERNAL MEDICINE 61 巻 ( 2 ) 頁： 233 - 236 2022年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本内科学会

We herein report a case of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) triggered by COVID-19. An 87-year-old woman tested positive for COVID-19 on a polymerase chain reaction test, and computed tomography revealed ground-glass opacity (GGO) superimposed on a background pattern consistent with usual interstitial pneumonia. Considering these data, we diagnosed her with AE-IPF. She experienced worsening of dyspnea and expansion of the GGO. Therefore, we introduced high-dose steroids (methylprednisolone 250 mg/day for 3 days). After the treatment, the pulmonary infiltrates improved. She was discharged from our hospital without severe disability. High-dose steroids can be a viable treatment option for AE-IPF triggered by COVID-19.

DOI： 10.2169/internalmedicine.8163-21

Size and surface modification of silica nanoparticles affect the severity of lung toxicity by modulating endosomal ROS generation in macrophages 国際誌

The Effect of Pirfenidone on the Prescription of Antibiotics and Antitussive Drugs in Patients With Idiopathic Pulmonary Fibrosis: A Post Hoc Exploratory Analysis of Phase III Clinical Trial. 査読有り国際誌

Suzuki A, Sakaguchi H, Sakamoto K, Ebina M, Azuma A, Ogura T, Taguchi Y, Suga M, Takahashi H, Sugiyama Y, Kudoh S, Nukiwa T, Miyazawa S, Kondoh Y

Chest 160 巻 ( 4 ) 頁： 1372 - 1376 2021年10月

Inoue Masahide, Sakamoto Koji, Suzuki Atsushi, Nakai Shinya, Ando Akira, Shiraki Yukihiko, Nakahara Yoshio, Omura Mika, Enomoto Atsushi, Nakase Ikuhiko, Sawada Makoto, Hashimoto Naozumi

PARTICLE AND FIBRE TOXICOLOGY 18 巻 ( 1 ) 頁： 21 - 21 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Particle and Fibre Toxicology

Background: As the application of silica nanomaterials continues to expand, increasing chances of its exposure to the human body and potential harm are anticipated. Although the toxicity of silica nanomaterials is assumed to be affected by their physio-chemical properties, including size and surface functionalization, its molecular mechanisms remain unclear. We hypothesized that analysis of intracellular localization of the particles and subsequent intracellular signaling could reveal a novel determinant of inflammatory response against silica particles with different physico-chemical properties. Results: We employed a murine intratracheal instillation model of amorphous silica nanoparticles (NPs) exposure to compare their in vivo toxicities in the respiratory system. Pristine silica-NPs of 50 nm diameters (50 nm-plain) induced airway-centered lung injury with marked neutrophilic infiltration. By contrast, instillation of pristine silica particles of a larger diameter (3 μm; 3 μm-plain) significantly reduced the severity of lung injury and neutrophilic infiltration, possibly through attenuated induction of neutrophil chemotactic chemokines including MIP2. Ex vivo analysis of alveolar macrophages as well as in vitro assessment using RAW264.7 cells revealed a remarkably lower cellular uptake of 3 μm-plain particles compared with 50 nm-plain, which is assumed to be the underlying mechanism of attenuated immune response. The severity of lung injury and neutrophilic infiltration was also significantly reduced after intratracheal instillation of silica NPs with an amine surface modification (50 nm-NH2) when compared with 50 nm-plain. Despite unchanged efficacy in cellular uptake, treatment with 50 nm-NH2 induced a significantly attenuated immune response in RAW264.7 cells. Assessment of intracellular redox signaling revealed increased reactive oxygen species (ROS) in endosomal compartments of RAW264.7 cells treated with 50 nm-plain when compared with vehicle-treated control. In contrast, augmentation of endosomal ROS signals in cells treated with 50 nm-NH2 was significantly lower. Moreover, selective inhibition of NADPH oxidase 2 (NOX2) was sufficient to inhibit endosomal ROS bursts and induction of chemokine expressions in cells treated with silica NPs, suggesting the central role of endosomal ROS generated by NOX2 in the regulation of the inflammatory response in macrophages that endocytosed silica NPs. Conclusions: Our murine model suggested that the pulmonary toxicity of silica NPs depended on their physico-chemical properties through distinct mechanisms. Cellular uptake of larger particles by macrophages decreased, while surface amine modification modulated endosomal ROS signaling via NOX2, both of which are assumed to be involved in mitigating immune response in macrophages and resulting lung injury.

DOI： 10.1186/s12989-021-00415-0