研究者詳細 - 阪本　考司

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

Impact of post-capillary pulmonary hypertension on mortality in interstitial lung disease 国際誌

Teramachi, R; Taniguchi, H; Kondoh, Y; Kimura, T; Kataoka, K; Yokoyama, T; Furukawa, T; Yagi, M; Sakamoto, K; Hashimoto, N; Hasegawa, Y

RESPIRATORY INVESTIGATION 59 巻 ( 3 ) 頁： 342 - 349 2021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：Respiratory Investigation

Background: Pulmonary hypertension (PH) influences mortality in patients with interstitial lung disease (ILD). Almost all studies on patients with ILD, have focused on the clinical impact of pre-capillary PH on survival. Therefore, little is known about the influence of post-capillary PH. We aimed to assess the prevalence of post-capillary PH and its clinical impact on survival in patients with ILD, followed by comparison with pre-capillary PH. Methods: This retrospective study enrolled 1152 patients with ILD who were diagnosed with PH using right heart catheterization between May 2007 and December 2015. We analyzed the demographics and composite outcomes (defined as death from any cause or lung transplantation) of patients with post-capillary PH and compared them with patients with pre-capillary PH. Results: Thirty-two (20%) of the 157 patients with ILD-PH were diagnosed with post-capillary PH. Patients with post-capillary PH had significantly lower modified Medical Research Council scores, higher diffusion capacity for carbon monoxide, higher resting PaO2, lower pulmonary vascular resistance (PVR), and higher lowest oxygen saturation during the 6-min walk test compared to those with pre-capillary PH. Cardiovascular diseases were associated with a higher risk of mortality in patients with post-capillary PH. Multivariate Cox proportional hazards analysis demonstrated no significant difference between the composite outcomes in pre-capillary and post-capillary PH, while PVR and the ILD Gender-Age-Physiology Index were significantly associated with the composite outcome. Conclusions: We found that approximately one-fifth of patients with ILD-PH were diagnosed with post-capillary PH, and that PVR and not post-capillary PH was associated with mortality.

DOI： 10.1016/j.resinv.2020.12.010

The Importance of Appropriate Diagnosis in the Practical Management of Chronic Obstructive Pulmonary Disease 国際誌

Hashimoto Naozumi, Wakahara Keiko, Sakamoto Koji

DIAGNOSTICS 11 巻 ( 4 ) 2021年4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：Diagnostics

Chronic obstructive pulmonary disease (COPD) is projected to continue to contribute to an increase in the overall worldwide burden of disease until 2030. Therefore, an accurate assessment of the risk of airway obstruction in patients with COPD has become vitally important. Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the American Thoracic Society (ATS) and European Respiratory Society (ERS), and the Japanese Respiratory Society (JRS) provide the criteria by which to diagnose COPD, many studies suggest that it is in fact underdiagnosed. Its prevalence increases, while the impact of COPD-related systemic comorbidities is also increasingly recognized in clinical aspects of COPD. Although a recent report suggests that spirometry should not be used to screen for airflow limitation in individuals without respiratory symptoms, the early detection of COPD in patients with no, or few, symptoms is an opportunity to provide appropriate management based on COPD guidelines. Clinical advances have been made in pharmacotherapeutic approaches to COPD. This article provides a current understanding of the importance of an appropriate diagnosis in the real-world management of COPD.

DOI： 10.3390/diagnostics11040618

Long noncoding RNA TINCR is a novel regulator of human bronchial epithelial cell differentiation state 査読有り国際共著国際誌

Omote Norihito, Sakamoto Koji, Li Qin, Schupp Jonas C., Adams Taylor, Ahangari Farida, Chioccioli Maurizio, DeIuliis Giuseppe, Hashimoto Naozumi, Hasegawa Yoshinori, Kaminski Naftali

PHYSIOLOGICAL REPORTS 9 巻 ( 3 ) 頁： e14727 2021年2月

Supplemental oxygen improves exercise capacity in IPF patients with exertional desaturation 査読有り国際誌

Arizono Shinichi, Furukawa Taiki, Taniguchi Hiroyuki, Sakamoto Koji, Kimura Tomoki, Kataoka Kensuke, Ogawa Tomoya, Watanabe Fumiko, Kondoh Yasuhiro

RESPIROLOGY 25 巻 ( 11 ) 頁： 1152 - 1159 2020年11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: The efficacy of supplemental oxygen during exercise remains unclear for patients with IPF, as there have been conflicting results from recent prospective studies with small sample sizes. Methods: This prospective, single-blind, randomized, crossover trial evaluated the efficacy of supplemental oxygen compared with placebo air during exercise in consecutive patients with IPF without resting hypoxaemia at initial evaluation. Patients with <90% SpO2 in a 6MWT using room air were randomly assigned to a CWRET at 80% of peak work rate with oxygen or placebo air gas via nasal cannula at 4 L/min. The primary endpoint was the effect of supplemental oxygen on endurance time. Results: We recruited 72 consecutive patients (median age: 66.5 years, % FVC: 84.6%, % DLCO: 61.4%). Supplemental oxygen significantly increased the endurance time (340–424 s; P < 0.001) and minimum SpO2 (88.0–94.0%; P < 0.001) compared with placebo air. Furthermore, supplemental oxygen significantly improved dyspnoea and leg fatigue. In a multivariate linear regression analysis, the endurance time on air was an independent explanatory variable of the improvement rate of endurance time (P = 0.02). Conclusion: In mild–moderate IPF with exercise-induced hypoxaemia even without resting hypoxaemia, supplemental oxygen during exercise improved the endurance time, desaturation and subjective symptoms. Patients with shorter endurance times with placebo air showed better improvement with supplemental oxygen.

DOI： 10.1111/resp.13829

Clinical burden of immune checkpoint inhibitor-induced pneumonitis 査読有り国際誌

Sakamoto Koji, Fukihara Jun, Morise Masahiro, Hashimoto Naozumi

RESPIRATORY INVESTIGATION 58 巻 ( 5 ) 頁： 305 - 319 2020年9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：Respiratory Investigation

Immune checkpoint inhibitors (ICIs) have been a breakthrough in medical oncology. However, many patients experience a novel type of adverse drug reaction that has a unique clinical presentation, called immune-related adverse events (irAEs). A breakdown of self-tolerance and an exaggerated autoimmune reaction by the host are assumed to be the underlying mechanisms. Therefore, special attention to the optimal diagnosis and management is required. Among the various effects of irAE, pneumonitis has been recognized as an important manifestation because of its high morbidity and mortality. As the application of ICIs is expanding to a wider variety of tumor types, as well as its use with cytotoxic agents and radiation, clinicians are highly likely to encounter this complication. In this review, we will summarize the current understanding of the underlying mechanisms, incidence, risk factors, optimal diagnostic workup, and management of ICI-related pneumonitis (IRP). We will also review fundamental information on drug-induced lung toxicity in the oncology setting. In addition, research perspectives focused on better risk stratification and management to avoid serious complications in the future are presented.

DOI： 10.1016/j.resinv.2020.05.008

肺線維症新規治療に関する基礎研究肺線維症の病態形成におけるメフリンの役割

中原義夫, 橋本直純, 阪本考司, 榎本篤

日本呼吸器学会誌 9 巻 ( 増刊 ) 頁： 139 - 139 2020年8月

Acute Exacerbation of Pleuroparenchymal Fibroelastosis Secondary to Allogenic Hematopoietic Stem Cell Transplantation.

Murakami Y, Sakamoto K, Okumura Y, Suzuki A, Mii S, Sato M, Yokoi T, Hashimoto N, Hasegawa Y

Internal medicine (Tokyo, Japan) 2020年7月

Reply to "Prognostic Impact and Risk Factors of Immune-Related Pneumonitis in Patients With NoneSmall-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 21 巻 ( 3 ) 頁： E205 - E205 2020年5月

Acute exacerbations of fibrotic interstitial lung diseases 査読有り国際誌

Suzuki Atsushi, Kondoh Yasuhiro, Brown Kevin K., Johkoh Takeshi, Kataoka Kensuke, Fukuoka Junya, Kimura Tomoki, Matsuda Toshiaki, Yokoyama Toshiki, Fukihara Jun, Ando Masahiko, Tanaka Tomonori, Hashimoto Naozumi, Sakamoto Koji, Hasegawa Yoshinori

RESPIROLOGY 25 巻 ( 5 ) 頁： 525 - 534 2020年5月

High-flow nasal cannula therapy for acute respiratory failure in patients with interstitial pneumonia: a retrospective observational study 国際誌

Omote, N; Matsuda, N; Hashimoto, N; Nishida, K; Sakamoto, K; Ando, A; Nakahara, Y; Nishikimi, M; Higashi, M; Matsu, S; Hasegawa, Y

NAGOYA JOURNAL OF MEDICAL SCIENCE 82 巻 ( 2 ) 頁： 301 - 313 2020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：Nagoya Journal of Medical Science

High-flow nasal cannula (HFNC) oxygen is a therapy that has demonstrated survival benefits in acute respiratory failure (ARF). However, the role of HFNC in ARF due to interstitial pneumonia (IP) is unknown. The aim of this study was to compare the effects of HFNC therapy and non-invasive positive pressure ventilation (NPPV) in ARF due to IP. This retrospective observational study included 32 patients with ARF due to IP who were treated with HFNC (n = 13) or NPPV (n = 19). The clinical characteristics, intubation rate and 30-day mortality were analyzed and compared between the HFNC group and the NPPV group. Predictors of 30-day mortality were evaluated using a logistic regression model. HFNC group showed higher mean arterial blood pressure (median 92 mmHg; HFNC group vs 74 mmHg; NPPV group) and lower APACHEII score (median 22; HFNC group vs 27; NPPV group) than NPPV group. There was no significant difference in the intubation rate at day 30 between the HFNC group and the NPPV group (8% vs 37%: p = 0.069); the mortality rate at 30 days was 23% and 63%, respectively. HFNC therapy was a significant determinant of 30-day mortality in univariate analysis, and was confirmed to be an independent significant determinant of 30-day mortality in multivariate analysis (odds ratio, 0.148; 95% confidence interval, 0.025-0.880; p = 0.036). Our findings suggest that HFNC therapy can be a possible option for respiratory management in ARF due to IP. The results observed here warrant further investigation of HFNC therapy in randomized control trials.

DOI： 10.18999/nagjms.82.2.301

Renewed Japanese spirometric reference variables and risk stratification for postoperative outcomes in COPD patients with resected lung cancer 査読有り国際誌

Okada Yu, Hashimoto Naozumi, Iwano Shingo, Kawaguchi Koji, Fukui Takayuki, Sakamoto Koji, Wakai Kenji, Yokoi Kohei, Hasegawa Yoshinori

NAGOYA JOURNAL OF MEDICAL SCIENCE 81 巻 ( 3 ) 頁： 427 - 438 2019年8月

Repressive role of stabilized hypoxia inducible factor 1 alpha expression on transforming growth factor beta-induced extracellular matrix production in lung cancer cells 査読有り国際誌

Ando Akira, Hashimoto Naozumi, Sakamoto Koji, Omote Norihito, Miyazaki Shinichi, Nakahara Yoshio, Imaizumi Kazuyoshi, Kawabe Tsutomu, Hasegawa Yoshinori

CANCER SCIENCE 110 巻 ( 6 ) 頁： 1959 - 1973 2019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：Cancer Science

Activation of transforming growth factor β (TGF-β) combined with persistent hypoxia often affects the tumor microenvironment. Disruption of cadherin/catenin complexes induced by these stimulations yields aberrant extracellular matrix (ECM) production, characteristics of epithelial-mesenchymal transition (EMT). Hypoxia-inducible factors (HIF), the hallmark of the response to hypoxia, play differential roles during development of diseases. Recent studies show that localization of cadherin/catenin complexes at the cell membrane might be tightly regulated by protein phosphatase activity. We aimed to investigate the role of stabilized HIF-1α expression by protein phosphatase activity on dissociation of the E-cadherin/β-catenin complex and aberrant ECM expression in lung cancer cells under stimulation by TGF-β. By using lung cancer cells treated with HIF-1α stabilizers or carrying doxycycline-dependent HIF-1α deletion or point mutants, we investigated the role of stabilized HIF-1α expression on TGF-β-induced EMT in lung cancer cells. Furthermore, the underlying mechanisms were determined by inhibition of protein phosphatase activity. Persistent stimulation by TGF-β and hypoxia induced EMT phenotypes in H358 cells in which stabilized HIF-1α expression was inhibited. Stabilized HIF-1α protein expression inhibited the TGF-β-stimulated appearance of EMT phenotypes across cell types and species, independent of de novo vascular endothelial growth factor A (VEGFA) expression. Inhibition of protein phosphatase 2A activity abrogated the HIF-1α-induced repression of the TGF-β-stimulated appearance of EMT phenotypes. This is the first study to show a direct role of stabilized HIF-1α expression on inhibition of TGF-β-induced EMT phenotypes in lung cancer cells, in part, through protein phosphatase activity.

DOI： 10.1111/cas.14027