Faculty Profiles - SAKAMOTO Koji

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 Vol. 61 ( 2 ) page： 233 - 236 2022

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Internal Medicine

<p>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. </p>

DOI： 10.2169/internalmedicine.8163-21

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. Reviewed International journal

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 Vol. 160 ( 4 ) page： 1372 - 1376 2021.10

Size and surface modification of silica nanoparticles affect the severity of lung toxicity by modulating endosomal ROS generation in macrophages. International journal

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

Particle and fibre toxicology Vol. 18 ( 1 ) page： 21 - 21 2021.6

Language：English Publishing type：Research paper (scientific journal)

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. International journal

Ryo Teramachi, Hiroyuki Taniguchi, Yasuhiro Kondoh, Tomoki Kimura, Kensuke Kataoka, Toshiki Yokoyama, Taiki Furukawa, Mitsuaki Yagi, Koji Sakamoto, Naozumi Hashimoto, Yoshinori Hasegawa

Respiratory investigation Vol. 59 ( 3 ) page： 342 - 349 2021.5

Language：English Publishing type：Research paper (scientific journal)

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. International journal

Naozumi Hashimoto, Keiko Wakahara, Koji Sakamoto

Diagnostics (Basel, Switzerland) Vol. 11 ( 4 ) 2021.4

Language：English Publishing type：Research paper (scientific journal)

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 Reviewed International coauthorship International journal

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 Vol. 9 ( 3 ) page： e14727 2021.2

Supplemental oxygen improves exercise capacity in IPF patients with exertional desaturation. Reviewed International journal

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

Respirology (Carlton, Vic.) Vol. 25 ( 11 ) page： 1152 - 1159 2020.11

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Koji Sakamoto, Jun Fukihara, Masahiro Morise, Naozumi Hashimoto

Respiratory investigation Vol. 58 ( 5 ) page： 305 - 319 2020.9

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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 Vol. 9 ( 増刊 ) page： 139 - 139 2020.8

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) 2020.7

Reply to "Prognostic Impact and Risk Factors of Immune-Related Pneumonitis in Patients With Non-Small-Cell Lung Cancer Who Received Programmed Death-1 Inhibitors". Reviewed International journal

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

Clinical lung cancer Vol. 21 ( 3 ) page： E205 - E205 2020.5

Acute exacerbations of fibrotic interstitial lung diseases. Reviewed International journal

Suzuki A, Kondoh Y, Brown KK, Johkoh T, Kataoka K, Fukuoka J, Kimura T, Matsuda T, Yokoyama T, Fukihara J, Ando M, Tanaka T, Hashimoto N, Sakamoto K, Hasegawa Y

Respirology (Carlton, Vic.) Vol. 25 ( 5 ) page： 525 - 534 2020.5

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

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

Nagoya journal of medical science Vol. 82 ( 2 ) page： 301 - 313 2020.5

＜Editors' Choice＞ Renewed Japanese spirometric reference variables and risk stratification for postoperative outcomes in COPD patients with resected lung cancer. Reviewed International journal

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

Nagoya journal of medical science Vol. 81 ( 3 ) page： 427 - 438 2019.8

Language：English Publishing type：Research paper (scientific journal)

Although the lower limit of normal (LLN) of FEV1/FVC detects at-risk patients for postoperative outcomes among Japanese chronic obstructive pulmonary disease (COPD) patients with resected lung cancer, there was a lack of a Japanese reference equation to calculate the LLN of FEV1/FVC. Renewed Japanese spirometric reference variables might enable us to verify clinical impact of the LLN of FEV1/FVC among the Japanese population. To evaluate the clinical impact of the LLN of FEV1/FVC by using this renewed reference, data were retrospectively analyzed from 609 newly diagnosed lung cancer patients who had undergone thoracic surgery between 2006 and 2011. The combined assessment of the 0.70 fixed ratio and the LLN of the FEV1/FVC ratio classified the 609 subjects into the COPD (214 subjects), non-COPD (337 subjects), and in-between (58 subjects) groups, respectively. All of the relative odds ratios (ORs) of postoperative outcomes for the comparison between the in-between and non-COPD groups did not show significant confidence intervals (CIs). On the other hand, the adjusted ORs of postoperative outcomes for the COPD group versus the non-COPD group were 2.840 (95% CI: 1.824-4.421) for prolonged oxygen therapy (POT), 1.836 (95% CI: 1.166-2.890) for prolonged postoperative stays, and 1.637 (95% CI: 1.007-2.663) for combined complications. Adjusted comparisons of POT between the in-between and COPD groups also showed a significant relative OR of 2.984 (95% CI: 1.447-6.153). A standardized assessment of the LLN of FEV1/FVC by a renewed Japanese spirometric reference provides risk stratification for postoperative outcomes in the population.

DOI： 10.18999/nagjms.81.3.427