Faculty Profiles - TSUKAHARA Hirokazu

Papers - TSUKAHARA Hirokazu

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Novel Lung Growth Strategy with Biological Therapy Targeting Airway Remodeling in Childhood Bronchial Asthma. Reviewed International journal

Mitsuru Tsuge, Masanori Ikeda, Hirokazu Tsukahara

Children (Basel, Switzerland) 9 ( 8 ) 2022.8

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Anti-inflammatory therapy, centered on inhaled steroids, suppresses airway inflammation in asthma, reduces asthma mortality and hospitalization rates, and achieves clinical remission in many pediatric patients. However, the spontaneous remission rate of childhood asthma in adulthood is not high, and airway inflammation and airway remodeling persist after remission of asthma symptoms. Childhood asthma impairs normal lung maturation, interferes with peak lung function in adolescence, reduces lung function in adulthood, and increases the risk of developing chronic obstructive pulmonary disease (COPD). Early suppression of airway inflammation in childhood and prevention of asthma exacerbations may improve lung maturation, leading to good lung function and prevention of adult COPD. Biological drugs that target T-helper 2 (Th2) cytokines are used in patients with severe pediatric asthma to reduce exacerbations and airway inflammation and improve respiratory function. They may also suppress airway remodeling in childhood and prevent respiratory deterioration in adulthood, reducing the risk of COPD and improving long-term prognosis. No studies have demonstrated a suppressive effect on airway remodeling in childhood severe asthma, and further clinical trials using airway imaging analysis are needed to ascertain the inhibitory effect of biological drugs on airway remodeling in severe childhood asthma. In this review, we describe the natural prognosis of lung function in childhood asthma and the risk of developing adult COPD, the pathophysiology of allergic airway inflammation and airway remodeling via Th2 cytokines, and the inhibitory effect of biological drugs on airway remodeling in childhood asthma.

DOI： 10.3390/children9081253

Correlation between national surveillance and search engine query data on respiratory syncytial virus infections in Japan. Reviewed International journal

Kazuhiro Uda, Hideharu Hagiya, Takashi Yorifuji, Toshihiro Koyama, Mitsuru Tsuge, Masato Yashiro, Hirokazu Tsukahara

BMC public health 22 ( 1 ) 1517 - 1517 2022.8

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The respiratory syncytial virus (RSV) disease burden is significant, especially in infants and children with an underlying disease. Prophylaxis with palivizumab is recommended for these high-risk groups. Early recognition of a RSV epidemic is important for timely administration of palivizumab. We herein aimed to assess the correlation between national surveillance and Google Trends data pertaining to RSV infections in Japan. METHODS: The present, retrospective survey was performed between January 1, 2018 and November 14, 2021 and evaluated the correlation between national surveillance data and Google Trends data. Joinpoint regression was used to identify the points at which changes in trends occurred. RESULTS: A strong correlation was observed every study year (2018 [r = 0.87, p < 0.01], 2019 [r = 0.83, p < 0.01], 2020 [r = 0.83, p < 0.01], and 2021 [r = 0.96, p < 0.01]). The change-points in the Google Trends data indicating the start of the RSV epidemic were observed earlier than by sentinel surveillance in 2018 and 2021 and simultaneously with sentinel surveillance in 2019. No epidemic surge was observed in either the Google Trends or the surveillance data from 2020. CONCLUSIONS: Our data suggested that Google Trends has the potential to enable the early identification of RSV epidemics. In countries without a national surveillance system, Google Trends may serve as an alternative early warning system.

DOI： 10.1186/s12889-022-13899-y

Sports participation and preterm birth: a nationwide birth cohort in Japan. Reviewed International journal

Kei Tamai, Naomi Matsumoto, Akihito Takeuchi, Makoto Nakamura, Kazue Nakamura, Misao Kageyama, Yosuke Washio, Hirokazu Tsukahara, Takashi Yorifuji

Pediatric research 92 ( 2 ) 572 - 579 2022.8

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

BACKGROUND: Children born preterm may be less physically active than children born term because of neurocognitive problems, reduced lung function, and poor physical fitness. We evaluated sports participation of children and adolescents who had been born preterm (<37 weeks) and early term (37-38 weeks) in 2001. METHODS: Data from a nationwide longitudinal survey (n = 47,015, including 2375 children born preterm) were analyzed. As indicators of sports participation, we used responses to questions about participation in sports clubs at 7 and 10 years old and in extracurricular school sports at 15 years old. RESULTS: Children born very preterm (25-31 weeks) and moderately to late preterm (32-36 weeks) were less likely to participate in sports clubs at 7, 10, and 15 years old than children born full term (39-41 weeks). Compared with children born full term, the adjusted risk ratios for participation in extracurricular school sports at 15 years old were 0.86 (95% confidence interval: 0.75-0.98) for children born very preterm, 0.92 (0.88-0.97) for children born moderately to late preterm, and 1.00 (0.98-1.02) for children born early term. CONCLUSIONS: Our findings suggest that preterm birth is associated with less participation in organized sports during childhood and adolescence than full-term birth. IMPACT: Research investigating associations between preterm birth and physical activity among children born in the 2000s is limited. This study shows that preterm birth was associated with less participation in organized sports during childhood and adolescence than full-term birth, especially in boys, and the participation in organized sports of children born preterm decreased as gestation shortened. During childhood, boys born early term were also less likely to participate in organized sports than boys born full term, suggesting a continuum with preterm births. These findings offer important additional insights into the limited evidence available for predicting future health outcomes for preterm infants.

DOI： 10.1038/s41390-021-01808-9

Preterm birth and Kawasaki disease: a nationwide Japanese population-based study. Reviewed International journal

Akihito Takeuchi, Takahiro Namba, Naomi Matsumoto, Kei Tamai, Kazue Nakamura, Makoto Nakamura, Misao Kageyama, Toshihide Kubo, Hirokazu Tsukahara, Takashi Yorifuji

Pediatric research 92 ( 2 ) 557 - 562 2022.8

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

BACKGROUND: Previous studies showed that preterm birth increased the risk for hospital admissions in infancy and childhood due to some acute diseases. However, the risk of preterm children developing Kawasaki disease remains unknown. In the present study, we investigate whether preterm birth increased the morbidity of Kawasaki disease. METHODS: We included 36,885 (34,880 term and 2005 preterm) children born in 2010 in Japan. We examined the association between preterm birth and hospitalization due to Kawasaki disease using a large nationwide survey in Japan. RESULTS: In log-linear regression models that were adjusted for children's characteristics (sex, singleton birth, and parity), parental characteristics (maternal age, maternal smoking, paternal smoking, maternal education, and paternal income), and residential area, preterm infants were more likely to be hospitalized due to Kawasaki disease (adjusted risk ratio: 1·55, 95% confidence interval: 1.01-2.39). We then examined whether breastfeeding status modified the potential adverse effects of preterm birth on health outcome. Preterm infants with partial breastfeeding or formula feeding had a significantly higher risk of hospitalization due to Kawasaki disease compared with term infants with exclusive breastfeeding. CONCLUSIONS: Preterm infants were at a high risk for Kawasaki disease, and exclusive breastfeeding might prevent this disease among preterm infants. IMPACT: Previous studies showed that preterm birth increased the risk for hospital admissions in infancy and childhood due to some acute diseases, however, the risk of preterm children developing Kawasaki disease remains unknown. This Japanese large population-based study showed that preterm infants were at a high risk for Kawasaki disease for the first time. Furthermore, this study suggested that exclusively breastfeeding might prevent Kawasaki disease among preterm infants.

DOI： 10.1038/s41390-021-01780-4

褐色細胞腫との鑑別が問題になった本態性高血圧の一例

宮原宏幸, 長谷川高誠, 塚原宏一

日本小児高血圧研究会誌 18 ( 1 ) 29 - 36 2022.8

Language：Japanese Publisher：日本小児高血圧研究会

【背景】一過性の著明な血圧上昇をきたし種々の身体症状を呈する症例において,褐色細胞腫の可能性は考慮する必要があるが,偽性褐色細胞腫との鑑別を要することもある.他方,その他の疾患と悩まれることは多くないが,今回我々は本態性高血圧に加えて精神的要因が関与したことにより褐色細胞腫に類似した症状を呈した症例を経験したため報告する.【症例】生来健康な男児で肥満はなかった.15歳時に学校で誘因なく発作的に胸部違和感を自覚した後上肢の脱力をきたし,更に意識混濁した.その際に保健室で測定された収縮期血圧は200mmHgを超えていた.同様のエピソードを反復したため当院に紹介された.来院時の血圧は140-150/70-80mmHg程度であった.問診では,学校生活での強い心理的ストレスの他,塩分摂取過多が疑われた.鑑別疾患として褐色細胞腫や偽性褐色細胞腫も考えられたが,意識混濁の身体症状を伴ったためてんかんの可能性も検討した.メタネフリンやカテコラミンの測定値や画像検査で異常はなく,上記エピソードが起こった際の心電図や脳波所見にも異常はなかった.他方,brachial-ankle Pulse Wave Velocityは両側とも高値であった.また,意識混濁を含む身体症状は精神科より解離性障害が疑われた.これらのことから,本態性高血圧が背景にあり,精神的要因が加わって一過性に高血圧になった可能性を考えた.食事指導とアムロジピンを少量から開始し増量した他,精神科からはクロチアゼパムが処方された.その後しばらくは,上記と同様のエピソードを繰り返し何度か当院に救急搬送されたが,次第に症状は落ち着いた.【考察】本症例は,褐色細胞腫に類似した症状を呈したが,身体症状として意識混濁を伴った点も特徴的であった.意識混濁は褐色細胞腫や偽性褐色細胞腫の身体症状としては考えにくく,てんかん性疾患も考えたが否定的であった.精神的要因で身体症状を伴って一過性に高血圧を呈することはあるが,その際の血圧上昇の程度は軽度とされている.このため,精神症状のみでは本症例の症状を説明できなかったが,本態性高血圧が背景にあり,解離様の精神症状が加わったことで褐色細胞腫類似の症状を呈したものと考えることで症状が説明づけられた.(著者抄録)

新生児領域における酸化ストレス制御の意義

塚原宏一, 宮原宏幸, 鷲尾洋介, 津下充, 馬場健児

日本小児高血圧研究会誌 18 ( 1 ) 10 - 18 2022.8

Language：Japanese Publisher：日本小児高血圧研究会

酸化ストレスは、内部・外部刺激により生体内で活性酸素群(活性窒素も含む)が抗酸化システムで捕捉しきれないほど過剰に生じる状況である。酸化ストレス亢進は血管内皮障害と深く関連する。とりわけ、血管内皮での一酸化窒素(nitric oxide:NO)生成は生体のレドックス環境を保持するうえで必須である。酸化ストレス亢進はarginineを基質とするNO合成を抑制し、内因性NO合成酵素阻害因子であるasymmetric dimethylarginine(ADMA)の生成を刺激する。新生児の急速進行性疾患、慢性遷延性疾患ではしばしば酸化ストレスが増幅され、生体の構造や機能が酸化劣化を受けて、組織障害が不可逆的に進展する。これらの疾患の治療や管理において酸化ストレスを制御することは重要である。そのためには酸化ストレスの病態生理、それへの防御機制を把握し、特異的マーカーを用いて患者の酸化ストレス環境を非～低侵襲的に評価することが必要である。新生児医療の現場で実施される種々の治療は、酸化ストレス制御を目指すものでもある。その中で、母乳はNO、thioredoxin-1などの抗酸化因子を多量に含有し、酸化ストレス過剰病態の抑止に有効と推定される。今後は、"レドックス"に関連してより特異性の高い細胞機能修飾薬が開発され、それらが重症疾患への集学治療の中に組み込まれていくことが期待される。(著者抄録)

親子並行面接が奏功した抜毛症の女児例

椙原彰子, 重安良恵, 堀内真希子, 田中知絵, 藤井智香子, 岡田あゆみ, 塚原宏一

小児心身症研究 ( 28 ) 16 - 23 2022.6

Language：Japanese Publisher：日本小児心身医学会-中国四国地方会

抜毛症は、繰り返し体毛を抜くことと、これを減らそう・やめようとする試みが特徴の、身体に焦点化した反復行動である。学童期から思春期に多く、抜毛によって満足や快感、安心感を得ることがあるとされる。本報告では、抜毛症女子の親子並行面接過程を振り返り、治療の意義を考察する。患児は、学校で過剰適応な行動が指摘されており、面接でも自分の希望を言うことは少なかった。治療が進むにつれて自ら遊びを選ぶなどの自己表現が増えた。また、箱庭療法や遊戯療法で繰り返し「家」を表現し、環境への信頼を獲得した。母は、心療内科治療歴があり、育児困難感や夫婦関係の問題を抱えていた。母面接では、抜毛の背景を説明し、母の苦労を傾聴しながら、母の対応や患児の変化を肯定的にフィードバックした。患児は学校でも自己主張が可能となり、抜毛は減少した。母も患児の成長を語るようになった。親子並行面接の構造と家族支援の視点が母子を支えたと考えた。(著者抄録)

Author Correction: Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways. Reviewed International journal

Hiroyuki Miyahara, Kosei Hasegawa, Masato Yashiro, Toshiaki Ohara, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa, Hirokazu Tsukahara

Scientific reports 12 ( 1 ) 8026 - 8026 2022.5

Terry's nails in an infant with liver cirrhosis. Reviewed International journal

Kazuhiro Uda, Mitsuru Tsuge, Kenji Shigehara, Masato Yashiro, Hirokazu Tsukahara

Archives of disease in childhood 107 ( 5 ) 485 - 485 2022.5

宇田和宏, 塚原宏一

岡山医学会雑誌 134 ( 1 ) 48 - 51 2022.4

宇田和宏, 塚原宏一

岡山医学会雑誌 134 ( 1 ) 48 - 51 2022.4

Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways. Reviewed International journal

Hiroyuki Miyahara, Kosei Hasegawa, Masato Yashiro, Toshiaki Ohara, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa, Hirokazu Tsukahara

Scientific reports 12 ( 1 ) 4819 - 4819 2022.3

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Under normal conditions, fasting results in decreased protein disulfide isomerase (PDI) activity and accumulation of unfolded proteins, leading to the subsequent activation of the unfolded protein response (UPR)/autophagy signaling pathway to eliminate damaged mitochondria. Fasting also induces upregulation of thioredoxin-interacting protein (TXNIP) expression and mice deficient of this protein (TXNIP-KO mice) was shown to develop severe hypoglycemia, hyperlipidemia and liver steatosis (LS). In the present study, we aimed to determine the role of TXNIP in fasting-induced LS by using male TXNIP-KO mice that developed LS without severe hypoglycemia. In TXNIP-KO mice, fasting induced severe microvesicular LS. Examinations by transmission electron microscopy revealed mitochondria with smaller size and deformities and the presence of few autophagosomes. The expression of β-oxidation-associated genes remained at the same level and the level of LC3-II was low. PDI activity level stayed at the original level and the levels of p-IRE1 and X-box binding protein 1 spliced form (sXBP1) were lower. Interestingly, treatment of TXNIP-KO mice with bacitracin, a PDI inhibitor, restored the level of LC3-II after fasting. These results suggest that TXNIP regulates PDI activity and subsequent activation of the UPR/autophagy pathway and plays a protective role in fasting-induced LS.

DOI： 10.1038/s41598-022-08791-z

SLEにおけるTAC、MMF併用中の下痢と急性腎障害

奥村美紗, 宮原宏幸, 茂原研司, 斎藤有希恵, 津下充, 八代将登, 塚原宏一

小児科診療 85 ( 2 ) 253 - 255 2022.2

Language：Japanese Publisher：(株)診断と治療社

症例は全身性エリテマトーデスの18歳女性。タクロリムス(TAC)、ミコフェノール酸モフェチル(MMF)併用下に寛解状態にあった。急性胃腸炎を機に腎機能が低下し、いったん軽快した下痢の再燃および血球減少を認めた。TAC、MMF相互の副作用により両薬剤の血中濃度が上昇し有害事象が出現したと考えられ、TAC減量により症状は改善した。TAC、MMF2剤併用中に胃腸炎に罹患したときには、特異な血中濃度の変動に注意する必要がある。(著者抄録)

Urinary Protein-to-creatinine Ratios Predict Recurrence in Pediatric and Young Adult Cases of Minimal Change Nephrotic Syndrome. Reviewed

Hiroyuki Miyahara, Takayuki Miyai, Kunihiko Aya, Hirokazu Tsukahara

Acta medica Okayama 76 ( 1 ) 41 - 49 2022.2

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

High-dose steroids are required for the treatment of minimal change nephrotic syndrome (MCNS), especially for episodes of recurrence. Predicting and avoiding recurrence can help reduce the steroid dose, but prediction is currently difficult. We herein examined whether changes in laboratory data, especially the urinary protein- to-creatinine ratio (UTP/UCr), can predict clinical recurrence. We also assessed differences in clinical features between children and young adults. We included 36 patients with MCNS; for each case, we retrospectively studied laboratory data during stable remission and pre-recurrence, with the "stable" period defined as all but the 6 weeks before recurrence, and pre-recurrence defined as the 4±2 weeks before recurrence. UTP/UCr, serum albumin, etc. were measured every 5 years during stable periods. We divided patients into cohorts by age at recurrence, < 15 years and ≥ 15 years, and compared stable and pre-recurrence values for the two groups. UTP/UCr values during stable periods tended to be higher in younger patients. UTP/UCr and serum albumin showed statistically significant changes during pre-recurrence periods, but only in those aged ≥ 15 years. Thus, clinical features of recurrence differed depending on age. Signs of recurrence can be confirmed via UTP/UCr or serum albumin several weeks before recurrence in patients ≥ 15 years.

DOI： 10.18926/AMO/63207

The clinical course of Rathke's cleft cysts in pediatric patients: impact on growth and pubertal development. Reviewed

Yousuke Higuchi, Kosei Hasegawa, Toshihide Kubo, Hiroyuki Tanaka, Hirokazu Tsukahara

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 31 ( 1 ) 38 - 43 2022.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Society for Pediatric Endocrinology

Rathke's cleft cysts (RCCs) are non-neoplastic epithelial lesions in the sellar or suprasellar regions. RCCs are usually asymptomatic; however, some patients experience headaches, visual disturbances, and endocrine disorders. The best treatment for associated endocrinopathy remains elusive. We aimed to investigate the clinical course, magnetic resonance imaging findings, and response to therapy in 10 pediatric patients with RCCs and endocrinopathy. Growth impairment and precocious puberty were observed to be prevalent. One patient with suprasellar extension of RCC underwent surgery, while the others were treated medically. Of the nine patients, seven patients showed stable cyst size, while two patients displayed reduction in cyst size. Hormone replacement and gonadotropin suppression therapy were found to be effective. Imaging and endocrine follow-ups are warranted because of the potential for changes in the cyst size and hormonal changes.

DOI： 10.1297/cpe.2021-0034

A novel pathogenic variant p.Asp797Val in IFIH1 in a Japanese boy with overlapping Singleton-Merten syndrome and Aicardi-Goutières syndrome. Reviewed International journal

Kosei Hasegawa, Hiroyuki Tanaka, Natsuko Futagawa, Hiroyuki Miyahara, Yousuke Higuchi, Hirokazu Tsukahara

American journal of medical genetics. Part A 188 ( 1 ) 249 - 252 2022.1

Authorship：Last author Language：English

Pathogenic-activating variants of interferon induced with Helicase C domain 1 (IFIH1) cause Singleton-Merten (S-M) syndrome, which accompanies acro-osteolysis, loss of permanent teeth, and aortic calcification, as well as causing Aicardi-Goutières (A-G) syndrome, which shows progressive encephalopathy, spastic paraplegia, and calcification of basal ganglia. Recently, patients with overlapping syndromes presenting with features of S-M syndrome and A-G syndrome were reported. However, progression of clinical features of this condition has not been fully understood. We report a Japanese boy with a novel pathogenic IFIH1 variant who presented with clinical features of S-M syndrome and A-G syndrome.

DOI： 10.1002/ajmg.a.62478

Severe pediatric asthma with a poor response to omalizumab: a report of three cases and three-dimensional bronchial wall analysis. Reviewed International journal

Mitsuru Tsuge, Masanori Ikeda, Yoichi Kondo, Hirokazu Tsukahara

The Journal of international medical research 50 ( 1 ) 3000605211070492 - 3000605211070492 2022.1

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Omalizumab is used for the treatment of persistent severe allergic asthma in adults and children. However, some patients remain symptomatic even after omalizumab treatment. In bronchial asthma, chronic inflammation of the bronchial wall causes thickening of the airway wall, resulting from irreversible airway remodeling. Progression of airway remodeling causes airflow obstruction, leading to treatment resistance. We report three Japanese children with severe asthma who had a poor response to omalizumab treatment. They had a long period of inadequate management of asthma before initiating omalizumab. Even after omalizumab treatment, their symptoms persisted, and the parameters of spirometry tests did not improve. We hypothesized that omalizumab was less effective in these patients because airway wall remodeling had already progressed. We retrospectively evaluated the bronchial wall thickness using a three-dimensional bronchial wall analysis with chest computed tomography. The bronchial wall thickness was increased in these cases compared with six responders. Progressed airway wall thickness caused by airway remodeling may be associated with a poor response to omalizumab in children with severe asthma.

DOI： 10.1177/03000605211070492

Rapid Progression of Heterotopic Ossification in Severe Variant of Fibrodysplasia Ossificans Progressiva with p.Arg258Gly in ACVR1: A Case Report and Review of Clinical Phenotypes. Reviewed International journal

Kosei Hasegawa, Hiroyuki Tanaka, Natsuko Futagawa, Hiroyuki Miyahara, Hirokazu Tsukahara

Case reports in genetics 2022 5021758 - 5021758 2022

Authorship：Corresponding author Language：English

Fibrodysplasia ossificans progressiva (FOP) is a rare skeletal disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification. Malformation of the great toes appears at birth, while heterotopic ossification generally occurs during childhood and rarely occurs during infancy. Classical FOP results from the heterozygous p.Arg206His variant of the ACVR1 gene, which encodes Activin A receptor type 1. Recently, some atypical FOP patients with other ACVR1 gene variants and clinical features that are not observed in classical FOP patients have been reported. Herein, we describe a girl with severe FOP and multiple anomalies, including syndactyly of the hands and feet, nail agenesis, mandibular hypoplasia, heterotopic ossification occurring from infancy, and congenital cardiac malformation. In our patient, we identified de novo occurrence of the heterozygous p.Arg258Gly variant of ACVR1, which has previously been reported in only two severe FOP patients. Heterotopic ossification occurred earlier and more frequently compared with classical FOP patients. We present the time-series changes in heterotopic ossification in our patient and compare her clinical features with those of the previously reported patients with p.Arg258Gly. Our report deepens understanding of the clinical features in severe FOP with p.Arg258Gly and of FOP as a systemic disorder.

DOI： 10.1155/2022/5021758

Anti-high mobility group box 1 monoclonal antibody suppressed hyper-permeability and cytokine production in human pulmonary endothelial cells infected with influenza A virus. Reviewed International journal

Takahiro Namba, Mitsuru Tsuge, Masato Yashiro, Yukie Saito, Keyue Liu, Masahiro Nishibori, Tsuneo Morishima, Hirokazu Tsukahara

Inflammation research : official journal of the European Histamine Research Society ... [et al.] 70 ( 10-12 ) 1101 - 1111 2021.12

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: High mobility group box-1 (HMGB1) has been reported to be involved in influenza A virus-induced acute respiratory distress syndrome (ARDS). We studied the efficacy of an anti-HMGB1 mAb using an in vitro model of TNF-α stimulation or influenza A virus infection in human pulmonary microvascular endothelial cells (HMVECs). METHODS: Vascular permeability of HMVECs was quantified using the Boyden chamber assay under tumor necrosis factor-α (TNF-α) stimulation or influenza A virus infection in the presence of anti-HMGB1 mAb or control mAb. The intracellular localization of HMGB1 was assessed by immunostaining. Extracellular cytokine concentrations and intracellular viral mRNA expression were quantified by the enzyme-linked immunosorbent assay and quantitative reverse transcription PCR, respectively. RESULTS: Vascular permeability was increased by TNF-α stimulation or influenza A infection; HMVECs became elongated and the intercellular gaps were extended. Anti-HMGB1 mAb suppressed both the increase in permeability and the cell morphology changes. Translocation of HMGB1 to the cytoplasm was observed in the non-infected cells. Although anti-HMGB1 mAb did not suppress viral replication, it did suppress cytokine production in HMVECs. CONCLUSION: Anti-HMGB1 mAb might be an effective therapy for severe influenza ARDS.

DOI： 10.1007/s00011-021-01496-5

【周産期医学必修知識(第9版)】低カルシウム血症・低マグネシウム血症

長谷川高誠, 塚原宏一

周産期医学 51 ( 増刊 ) 880 - 882 2021.12

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