研究者業績

橋本 直純

ハシモト ナオズミ  (Naozumi Hashimoto)

基本情報

所属
藤田医科大学 呼吸器内科学 教授
学位
医学博士(名古屋大学)
PhD(Nagoya University)

J-GLOBAL ID
200901065007367549
researchmap会員ID
6000010184

論文

 143
  • Takayuki Okuji, Shintaro Iwama, Tomoko Kobayashi, Yoshinori Yasuda, Masaaki Ito, Ayana Yamagami, Masahiko Ando, Tetsunari Hase, Hirofumi Shibata, Takahiro Hatta, Xin Zhou, Takeshi Onoue, Yohei Kawaguchi, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Yuichi Ando, Naozumi Hashimoto, Hiroshi Arima
    Nagoya journal of medical science 86(3) 452-463 2024年8月  
    The presence of anti-thyroid antibodies (ATAs) is a biomarker for the development of thyroid dysfunction induced by anti-programmed cell death-1 antibodies (PD-1-Abs). While patients with thyroid dysfunction reportedly showed better overall survival (OS), it remains unknown if ATAs at baseline can predict OS. Therefore, in this study, we examined the association of ATAs at baseline with OS in non-small cell lung cancer (NSCLC) patients with different levels of programmed cell death-1 ligand 1 (PD-L1) positivity associated with PD-1-Ab treatment efficacy. A total of 81 NSCLC patients treated with PD-1-Abs were evaluated for ATAs at baseline and prospectively for OS. Among the 81 patients, 49 and 32 patients had ≥50% (group A) and <50% (group B) PD-L1 positivity, respectively. Median OS did not differ significantly between patients with (n = 13) and without (n = 36) ATAs at baseline in group A. In contrast, median OS was significantly longer in patients with (n = 10) versus without (n = 22) ATAs at baseline in group B (not reached vs 378 days, respectively; 95% CI, 182 to 574 days, p = 0.049). These findings suggest that the presence of ATAs at baseline is a biomarker to predict better treatment efficacy of PD-1-Abs in NSCLC patients with low PD-L1 positivity, while the difference in OS in those with high PD-L1 positivity may be masked by increased tumor expression of PD-L1.
  • Jun Fukihara, Koji Sakamoto, Yoshiki Ikeyama, Taiki Furukawa, Ryo Teramachi, Kensuke Kataoka, Yasuhiro Kondoh, Naozumi Hashimoto, Makoto Ishii
    Respiratory research 25(1) 202-202 2024年5月10日  
    BACKGROUND: Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF. METHODS: Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed. RESULTS: mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11,194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time. CONCLUSIONS: Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.
  • Takuya Okamura, Sayako Morikawa, Tomoya Horiguchi, Kumiko Yamatsuta, Toshikazu Watanabe, Aki Ikeda, Yuri Maeda, Takuma Ina, Hideaki Takahashi, Ryoma Moriya, Yasuhiro Goto, Sumito Isogai, Naoki Yamamoto, Shotaro Okachi, Naozumi Hashimoto, Kazuyoshi Imaizumi
    Respiration; international review of thoracic diseases 2024年2月22日  
    INTRODUCTION: Increasing numbers of cases of mild asymptomatic pulmonary alveolar proteinosis (PAP) are being reported with the recent increase in chest computed tomography (CT). Bronchoscopic diagnosis of mild PAP is challenging because of the patchy distribution of lesions, which makes it difficult to obtain sufficient biopsy samples. Additionally, the pathological findings of mild PAP, particularly those that differ from severe PAP, have not been fully elucidated. This study aimed to clarify the pathological findings of mild PAP and the usefulness of optical biopsy using probe-based confocal laser endomicroscopy (pCLE). METHODS: We performed bronchoscopic optical biopsy using pCLE and tissue biopsy in five consecutive patients with PAP (three with mild PAP and two with severe PAP). We compared the pCLE images of mild PAP with those of severe PAP by integrating clinical findings, tissue pathology, and chest computed tomography images. RESULTS: pCLE images of PAP showed giant cells with strong fluorescence, amorphous substances, and thin alveolar walls. Images of affected lesions in mild PAP were equivalent to those obtained in arbitrary lung lesions in severe cases. All three patients with mild PAP spontaneously improved or remained stable after ≥3 years of follow-up. Serum autoantibodies to granulocyte-macrophage colony-stimulating factor were detected in all five cases. CONCLUSION: Optical biopsy using pCLE can yield specific diagnostic findings, even in patients with mild PAP. pCLE images of affected areas in mild and severe PAP showed similar findings, indicating that the dysfunction level of pathogenic alveolar macrophages in affected areas is similar between both disease intensities.
  • Ken Akao, Yuko Oya, Takaya Sato, Aki Ikeda, Tomoya Horiguchi, Yasuhiro Goto, Naozumi Hashimoto, Masashi Kondo, Kazuyoshi Imaizumi
    Exploration of targeted anti-tumor therapy 5(4) 826-840 2024年  
    Despite innovative advances in molecular targeted therapy, treatment strategies using immune checkpoint inhibitors (ICIs) for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) have not progressed significantly. Accumulating evidence suggests that ICI chemotherapy is inadequate in this population. Biomarkers of ICI therapy, such as programmed cell death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs), are not biomarkers in patients with EGFR mutations, and the specificity of the tumor microenvironment has been suggested as the reason for this. Combination therapy with PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors is a concern because of its severe toxicity and limited efficacy. However, early-stage NSCLC may differ from advanced-stage NSCLC. In this review, we comprehensively review the current evidence and summarize the potential of ICI therapy in patients with EGFR mutations after acquiring resistance to treatment with EGFR-tyrosine kinase inhibitors (TKIs) with no T790M mutation or whose disease has progressed on osimertinib.
  • Takahiro Inoue, Sumito Isogai, Naoki Yamamoto, Noriko Hiramatsu, Yoshikazu Niwa, Hideaki Takahashi, Yutaro Kimura, Tomoya Horiguchi, Yasuhiro Goto, Naozumi Hashimoto, Kazuyoshi Imaizumi
    Therapeutic advances in respiratory disease 18 17534666241254980-17534666241254980 2024年  
    BACKGROUND: Bronchial thermoplasty (BT) is a recently developed non-pharmacological therapy for refractory bronchial asthma. Although increasing evidence has suggested that BT is effective for various phenotypes of severe asthma, its safety and efficacy in patients with severe irreversible impaired lung function are unclear. OBJECTIVES: To assess the efficacy and safety of BT in patients with refractory asthma, including patients with a severely impaired forced expiratory volume in 1 second (FEV1). DESIGN: This was a single-center, retrospective, observational cohort study. METHODS: We retrospectively reviewed the medical records of 15 patients with refractory asthma (Global Initiative for Asthma step 4 or 5), including patients with severely impaired airflow limitation (% predicted pre-bronchodilator FEV1 <60%), who had undergone BT between June 2016 and January 2022. We analyzed the efficacy (change in asthma symptoms, exacerbation rate, pulmonary function, asthma medication, and serum inflammatory chemokine/cytokines before and after BT) and complications in all patients. We compared these data between patients with severe obstructive lung dysfunction [group 1(G1)] and patients with FEV1 ⩾ 60% [group 2 (G2)]. RESULTS: Six patients were in G1 and nine were in G2. Clinical characteristics, T2 inflammation, and concurrent treatment were equivalent in both groups. BT significantly improved asthma-related symptoms (measured using the Asthma Control Test and Asthma Quality of Life Questionnaire scores) in both groups. FEV1 was significantly improved in G1 but not in G2. Four patients in G2, but none in G1, experienced asthma exacerbation requiring additional systemic corticosteroids (including two requiring prolonged hospitalization) after BT. Long-term responders (patients who reduced systemic or inhaled corticosteroid without newly adding biologics in a follow-up > 2 years) of BT were identified in G1 and G2 (n = 2, 33.3% and n = 4, 44.4%, respectively). CONCLUSION: BT in patients with refractory asthma and severe airflow limitation is equally safe and efficacious as that in patients with moderate airflow limitation.

MISC

 118
  • Koji Sakamoto, Naozumi Hashimoto, Yasuhiro Kondoh, Kazuyoshi Imaizumi, Daisuke Aoyama, Takashi Kohnoh, Masaaki Kusunose, Motohiro Kimura, Tsutomu Kawabe, Hiroyuki Taniguchi, Yoshinori Hasegawa
    AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY 303(1) L43-L53 2012年7月  査読有り
    Sakamoto K, Hashimoto N, Kondoh Y, Imaizumi K, Aoyama D, Kohnoh T, Kusunose M, Kimura M, Kawabe T, Taniguchi H, Hasegawa Y. Differential modulation of surfactant protein D under acute and persistent hypoxia in acute lung injury. Am J Physiol Lung Cell Mol Physiol 303: L43-L53, 2012. First published May 4, 2012; doi:10.1152/ajplung.00061.2012.-Hypoxia contributes to the development of fibrosis with epithelial-mesenchymal transition (EMT) via stimulation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and de novo twist expression. Although hypoxemia is associated with increasing levels of surfactant protein D (SP-D) in acute lung injury (ALI), the longitudinal effects of hypoxia on SP-D expression in lung tissue injury/fibrosis have not been fully evaluated. Here, the involvement of hypoxia and SP-D modulation was evaluated in a model of bleomycin-induced lung injury. We also investigated the molecular mechanisms by which hypoxia might modulate SP-D expression in alveolar cells, by using a doxycycline (Dox)-dependent HIF-1 alpha expression system. Tissue hypoxia and altered SP-D levels were present in bleomycin-induced fibrotic lesions. Acute hypoxia induced SP-D expression, supported by the finding that Dox-induced expression of HIF-1 alpha increased SP-D expression. In contrast, persistent hypoxia repressed SP-D expression coupled with an EMT phenotype and twist expression. Long-term expression of HIF-1 alpha caused SP-D repression with twist expression. Ectopic twist expression repressed SP-D expression. The longitudinal observation of hypoxia and SP-D levels in ALI in vivo was supported by the finding that HIF-1 alpha expression stabilized by acute hypoxia induced increasing SP-D expression in alveolar cells, whereas persistent hypoxia induced de novo twist expression in these cells, causing repression of SP-D and acquisition of an EMT phenotype. Thus this is the first study to demonstrate the molecular mechanisms, in which SP-D expression under acute and persistent hypoxia in acute lung injury might be differentially modulated by stabilized HIF-1 alpha expression and de novo twist expression.
  • Masaki Matsuo, Naozumi Hashimoto, Noriyasu Usami, Kazuyoshi Imaizumi, Kenji Wakai, Tsutomu Kawabe, Kohei Yokoi, Yoshinori Hasegawa
    INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY 14(5) 560-564 2012年5月  査読有り
    Although inspiratory capacity (IC) is strongly associated with the disease severity of chronic obstructive pulmonary disease, there was no appropriate equation to compute predicted values for IC. Furthermore, whether assessment of IC can identify the risk of prolonged postoperative stay (PPS) in patients undergoing thoracic surgery also remains unclear. To evaluate whether %IC predicted, for which the new equation to compute the predicted values for IC was utilized, could be applied to identify the risk of PPS, we retrospectively analysed the cases of 412 patients who underwent thoracic surgery in Nagoya University Hospital. The multivariate analysis demonstrated that %IC predicted &lt; 85% was one of the most critical risk predictors for PPS (odds ratio, 1.65; 95% confidence intervals, 1.03-2.648) and, in particular, was independent of percentage predicted forced expiratory volume in 1 s (%FEV1)&lt; 80%. A combined assessment of ICFEV1 Low, defined as %IC predicted &lt;85% or %FEV1 &lt;80%, was able to identify more than double the number of patients with PPS, compared with %FEV1 &lt;80% alone (65.9 vs. 28.5%, respectively). This is the first study to demonstrate the significance of %IC predicted in screening for the risk for PPS in patients undergoing thoracic surgery.
  • Harunori Nakashima, Naozumi Hashimoto, Daisuke Aoyama, Takashi Kohnoh, Koji Sakamoto, Masaaki Kusunose, Kazuyoshi Imaizumi, Yoshihiro Takeyama, Mitsuo Sato, Tsutomu Kawabe, Yoshinori Hasegawa
    MOLECULAR CARCINOGENESIS 51(5) 400-410 2012年5月  査読有り
    Epithelialmesenchymal transition (EMT), which involves the persistent loss of epithelial markers and expression of mesenchymal markers, is assumed to have a critical role in not only tissue development during embryogenesis but also central mechanisms that enhance the invasive and metastatic ability of cancer cells. Twist has been identified to play an essential role in EMT-mediated tumor invasion and metastasis. Although recent studies suggest that twist expression levels in tissue specimens of lung cancer might be associated with prognosis, the expression of twist in lung cancer cells itself and its effect have not been fully evaluated. Here, we evaluated twist expression and its effect on phenotype alteration in lung cancer cell lines. Twist expression varied among human lung cancer cell lines. The lung cancer cell lines with high twist expression also tended to show a high vimentin/E-cadherin ratio, which was supported by a migration assay, in which high twist expression gave rise to high cell motility. Furthermore, in comparison to control cells, the lung cancer cells with ectopic expression of twist showed a significant phenotype alteration through EMT and an increasing ability to migrate in vitro, in part, due to a tenfold increase in matrix metalloproteinases activity and almost a 60% increase in modulation of focal adhesion kinase activity, although a contribution of microRNA appeared unlikely in our study. Our present analysis of twist expression in lung cancer provide clues to comprehensive understanding of the mechanisms, by which metastasis often develops in lung cancer. (c) 2011 Wiley Periodicals, Inc.
  • Koji Sakamoto, Hiroyuki Taniguchi, Yasuhiro Kondoh, Kenji Wakai, Tomoki Kimura, Kensuke Kataoka, Naozumi Hashimoto, Osamu Nishiyama, Yoshinori Hasegawa
    RESPIRATORY MEDICINE 106(3) 436-442 2012年3月  査読有り
    Backgrounds: Bronchoalveolar lavage (BAL) is generally regarded as a safe diagnostic procedure. However, acute exacerbation after BAL is increasingly recognized as a specific complication for patients with idiopathic pulmonary fibrosis (IPF). So far little is known about the correlation between BAL and acute exacerbation of IPF (AE-IPF). Methods: A cohort of 112 IPF patients at a single institution was analyzed retrospectively. We defined BAL-related AE-IPF as development of AE-IPF within 30 days after the procedure. The incidence rate of AE-IPF per person-month during the post-BAL period was compared with that after the post-BAL period. The relative risk was estimated as the former rate divided by the latter. We also reviewed the previous literature. Results: Four AE-IPF cases occurred during the 201 person-month post-BAL period. The risk of AE-IPF was significantly elevated within 30 days after BAL (rate ratio = 4.12; 95% Cl = 1.03-12.2). None of the 111 initial BAL procedures were followed by AE-IPF within a month. In a post hoc analysis, the relative risk of developing AE after second or later BAL procedures was estimated to be considerably higher (rate ratio = 9.10; 95% CI = 2.27-26.98). Twelve cases of BAL-induced AE-IPF were found in our study and in the literature review. Among them, nine showed moderate to severe functional impairment, and eight had either findings of leukocytosis, positive C-reactive protein, or neutrophilia in BAL. Conclusions: These results suggest that IPF patients should be carefully monitored after BAL, especially those with functional impairment or active inflammation. (C) 2011 Elsevier Ltd. All rights reserved.
  • 岩野 信吾, 長縄 慎二, 橋本 直純
    臨床放射線 57(1) 55-61 2012年1月  
  • Hashimoto I, Imaizumi K, Hashimoto N, Furukawa H, Noda Y, Kawabe T, Honda T, Ogawa T, Matsuo M, Imai N, Ito S, Sato M, Kondo M, Shimokata K, Hasegawa Y
    Respirology doi: 10.1111/j.1440-1843.2012.02286.x. 2012年  査読有り
  • Yuta Hayashi, Miyoko Matsushima, Toshinobu Nakamura, Masataka Shibasaki, Naozumi Hashimoto, Kazuyoshi Imaizumi, Kaoru Shimokata, Yoshinori Hasegawa, Tsutomu Kawabe
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 417(1) 169-174 2012年1月  査読有り
    The lung is a primary target for oxygen toxicity because of its constant exposure to high oxygen levels and environmental oxidants. Quercetin is one of the most commonly found dietary flavonoids, and it provides cytoprotective actions via activation of specific transcriptional factors and upregulation of endogenous defensive pathways. In the present study, we showed that quercetin increased the levels of heme oxygenase (HO)-1 expression and protected against hydrogen peroxide (H2O2)-induced cytotoxicity in lung epithelial cell lines. Quercetin suppressed H2O2-induced apoptotic events, including hypodiploid cells, activation of caspase 3 enzyme activity and lactate dehydrogenase release. This cytoprotective effect was attenuated by the addition of the HO inhibitor, tin protoporphyrin IX. In addition, the end products of heme metabolites catalyzed by HO-1, carbon monoxide and bilirubin, protect against H2O2-induced cytotoxicity in LA-4 cells. Quercetin may well be one of the promising substances to attenuate oxidative epithelial cell injury in lung inflammation. (C) 2011 Elsevier Inc. All rights reserved.
  • Yoshitaka Hibino, Masahiro Morise, Yasushi Ito, Takefumi Mizutani, Tadakatsu Matsuno, Satoru Ito, Naozumi Hashimoto, Mitsuo Sato, Masashi Kondo, Kazuyoshi Imaizumi, Yoshinori Hasegawa
    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 45(4) 684-691 2011年10月  査読有り
    To investigate the effects of capsaicinoids on airway anion transporters, we recorded and analyzed transepithelial currents inhuman airway epithelial Calu-3 cells. Application of capsaicin (100 mu M) attenuated vectorial anion transport, estimated as short-circuit currents (I(SC)), before and after stimulation by forskolin (10 mu M) with concomitant reduction of cytosolic cyclic AMP (cAMP) levels. The capsaicin-induced inhibition of I(SC) was also observed in the response to 8-bromo-cAMP (1 mM, a cell-permeable cAMP analog) and 3-isobutyl-1-methylxanthine (1 mM, an inhibitor of phosphodiesterases). The capsaicin-induced inhibition of I(SC) was attributed to suppression of bumetanide (an inhibitor of the basolateral Na(+)-K(+)-2 Cl(-) cotransporter 1)- and 4,4'-dinitrostilbene-2,2'-disulfonic acid (an inhibitor of basolateral HCO(3)(-)-dependent anion transporters)sensitive components, which reflect anion uptake via basolateral cAMP-dependent anion transporters. In contrast, capsaicin potentiated apical Cl(-) conductance, which reflects conductivity through the cystic fibrosis transmembrane conductance regulator, a cAMP-regulated Cl(-) channel. All these paradoxical effects of capsaicin were mimicked by capsazepine. Forskolin application also increased phosphorylated myosin phosphatase target subunit 1, and the phosphorylation was prevented by capsaicin and capsazepine, suggesting that these capsaicinoids assume aspects of Rho kinase inhibitors. We also found that the increments in apical Cl(-) conductance were caused by conventional Rho kinase inhibitors, Y-27632 (20 mu M) and HA-1077 (20 mu M), with selective inhibition of basolateral Na(+)-K(+)-2 Cl(-) cotransporter 1. Collectively, capsaicinoids inhibit cAMP-mediated anion transport through down-regulation of basolateral anion uptake, paradoxically accompanied by up-regulation of apical cystic fibrosis transmembrane conductance regulator-mediated anion conductance. The latter is mediated by inhibition of Rho-kinase, which is believed to interact with actin cytoskeleton.
  • Shigeki Saito, Takayuki Nakayama, Naozumi Hashimoto, Yasuhiko Miyata, Kensuke Egashira, Norihiko Nakao, Satoshi Nishiwaki, Minoru Hasegawa, Yoshinori Hasegawa, Tomoki Naoe
    AMERICAN JOURNAL OF PATHOLOGY 179(3) 1088-1094 2011年9月  査読有り
    Acute respiratory distress syndrome (ARDS) is a crippling disease with no effective therapy characterized by progressive dyspnea. Mesenchymal stem cells (MSCs) have emerged as a new therapeutic modality for ARDS because MSCs can attenuate inflammation and repair the damaged tissue by differentiating into several cell types. Macrophages participate in the development of ARDS; however, MSCs only weakly modulate macrophage function. The chemokine CCL2 is a potent inducer of macrophage recruitment and activation, and its expression is elevated in patients with ARDS. We established MSCs that are stably transduced by a lentiviral vector expressing 7ND, a dominant-negative inhibitor of CCL2, to enhance the therapeutic function of MSCs. 7ND-MSCs retained the innate properties of MSCs and produced a large amount of 7ND. Many 7ND-MSCs were detected in bleomycin-treated lungs (immunostaining 24 hours after injection), suggesting that MSCs could work as a drug delivery tool. Mice treated with 7ND-MSCs showed significantly milder weight loss, lung injury, collagen content, accumulation of inflammatory cells and inflammatory mediators that were induced by bleomycin, and subsequent survival benefit. No evidence of 7ND-MSC induced toxicity was observed during or after treatment. Thus, inhibiting the effects of macrophages may greatly enhance the ability of MSCs to effect lung repair in ARDS. (Am J Pathol 2011, 179:1088-1094; DOI: 10.1016/j.ajpath.2011.05.027)
  • 橋本 直純, 長谷川 好規
    呼吸器内科 20(2) 153-157 2011年8月  
  • Tsutomu Kawabe, Miyoko Matsushima, Naozumi Hashimoto, Kazuyoshi Imaizumi, Yoshinori Hasegawa
    NAGOYA JOURNAL OF MEDICAL SCIENCE 73(3-4) 69-78 2011年8月  招待有り
    The CD40 ligand/CD40 pathway is widely recognized for its prominent role in immune regulation and homeostasis. CD40, a member of the tumor necrosis factor receptor family, is expressed by antigen-presenting cells, as well as non-immune cells and tumors. The engagement of the CD40 and CD40 ligands, which are transiently expressed on T cells and other non-immune cells under inflammatory conditions, regulates a wide spectrum of molecular and cellular processes, including the initiation and progression of cellular and humoral adaptive immunity. Based on recent research findings, the engagement of the CD40 with a deregulated amount of CD40 ligand has been implicated in a number of inflammatory diseases. We will discuss the involvement of the CD40 ligand/CD40 interaction in the pathophysiology of inflammatory diseases, including autoimmune diseases, atherothrombosis, cancer, and respiratory diseases.
  • Nakamura T, Matsushima M, Hayashi Y, Shibasaki M, Imaizumi K, Hashimoto N, Shimokata K, Hasegawa Y, Kawabe T
    Am J Respir Cell Mol Biol 44(5) 614-620 2011年5月  査読有り
  • Nakamura T, Matsushima M, Hayashi Y, Shibasaki M, Imaizumi K, Hashimoto N, Shimokata K, Hasegawa Y, Kawabe T
    Am J Respir Cell Mol Biol 44(5) 614-620 2011年5月1日  査読有り
  • Mineo Kondo, Rikako Sanuki, Shinji Ueno, Yuji Nishizawa, Naozumi Hashimoto, Hiroshi Ohguro, Shuichi Yamamoto, Shigeki Machida, Hiroko Terasaki, Grazyna Adamus, Takahisa Furukawa
    PLOS ONE 6(5) e19911 2011年5月  査読有り
    Background: Paraneoplastic retinopathy (PR), including cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), is a progressive retinal disease caused by antibodies generated against neoplasms not associated with the eye. While several autoantibodies against retinal antigens have been identified, there has been no known autoantibody reacting specifically against bipolar cell antigens in the sera of patients with PR. We previously reported that the transient receptor potential cation channel, subfamily M, member 1 (TRPM1) is specifically expressed in retinal ON bipolar cells and functions as a component of ON bipolar cell transduction channels. In addition, this and other groups have reported that human TRPM1 mutations are associated with the complete form of congenital stationary night blindness. The purpose of the current study is to investigate whether there are autoantibodies against TRPM1 in the sera of PR patients exhibiting ON bipolar cell dysfunction. Methodology/Principal Findings: We performed Western blot analysis to identify an autoantibody against TRPM1 in the serum of a patient with lung CAR. The electroretinograms of this patient showed a severely reduced ON response with normal OFF response, indicating that the defect is in the signal transmission between photoreceptors and ON bipolar cells. We also investigated the sera of 26 patients with MAR for autoantibodies against TRPM1 because MAR patients are known to exhibit retinal ON bipolar cell dysfunction. Two of the patients were found to have autoantibodies against TRPM1 in their sera. Conclusion/Significance: Our study reveals TRPM1 to be one of the autoantigens targeted by autoantibodies in at least some patients with CAR or MAR associated with retinal ON bipolar cell dysfunction.
  • Nishiyama O, Taniguchi H, Kondoh Y, Takada K, Baba K, Saito H, Sugino Y, Yamamoto M, Ogasawara T, Kondo M, Imaizumi K, Hasegawa Y, Suzuki R, Shimokata K
    Anticancer Drugs 22(8) 811 2011年  査読有り
  • Kensuke Kataoka, Hiroyuki Taniguchi, Yasuhiro Kondoh, Kiminori Fujimoto, Masanori Kitaichi, Masashi Kondo, Naozumi Hashimoto, Takeshi Johkoh
    RESPIROLOGY 15 83-83 2010年11月  
  • Yoshihiro Takeyama, Mitsuo Sato, Mihoko Horio, Tetsunari Hase, Kenya Yoshida, Toshihiko Yokoyama, Harunori Nakashima, Naozumi Hashimoto, Yoshitaka Sekido, Adi F. Gazdar, John D. Minna, Masashi Kondo, Yoshinori Hasegawa
    CANCER LETTERS 296(2) 216-224 2010年10月  査読有り
    We found that among four master epithelial-to-mesenchymal transition (EMT)-inducing genes (ZEB1, SIP1, Snail, and Slug) ZEB1expression was most significantly correlated with the mesenchymal phenotype (high Vimentin and low E-cadherin expression) in non-small cell lung cancer (NSCLC) cell lines and tumors. Furthermore. ZEB1 knockdown with RNA interference in three NSCLC cell lines with high ZEB1 expression suppressed to varying degrees mass culture growth and liquid colony formation but in all cases dramatically suppressed soft agar colony formation. In addition, ZEB1 knockdown induced apoptosis in one of the three lines, indicating that the growth inhibitory effects of ZEB1 knockdown occurs in part through the activation of the apoptosis pathway. These results suggest that inhibiting ZEB1 function may be an attractive target for NSCLC therapeutic development. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
  • Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Kawabe T, Shimokata K, Hasegawa Y
    Am J Respir Cell Mol Biol 143 161-172 2010年7月  査読有り
    肺線維症を形成する線維化病変において血管内皮細胞がEndothelial-Mesenchymal transition(Endothelial-MT)を介して線維芽細胞の構成細胞になることをブレオマイシン肺線維症モデルを用いて初めて証明した論文である。
  • Usami N, Yokoi K, Hasegawa Y, Taniguchi H, Shindo J, Yamamoto M, Suzuki R, Imaizumi K, Kondo M, Shimokata K, Central Japan Lung, Study Group
    Int J Clin Oncol 15(6) 583-587 2010年  査読有り
  • Morise M, Y. Ito, T. Matsuno, Y. Hibino, T. Mizutani, S. Ito, N. Hashimoto, M. Kondo, K. Imaizumi, Y. Hasegawa
    Eur J Pharmacol. 635 204-211 2010年1月1日  査読有り
  • Toyohiro Honda, Kazuyoshi Imaizumi, Toyoharu Yokoi, Naozumi Hashimoto, Izumi Hashimoto, Tsutomu Kawabe, Masaki Matsuo, Shingo Iwano, Kaoru Shimokata, Yoshinori Hasegawa
    AMERICAN JOURNAL OF THE MEDICAL SCIENCES 339(1) 41-48 2010年1月  査読有り
    Background: T-helper (Th)-2 background in the lungs may flavor the development of pulmonary fibrosis. We hypothesized that usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), major pathologic patterns of chronic interstitial pneumonia, Would have different expression profiles of T(H)1 and T(H)2 chemokines. Methods: Total RNA was isolated from lung tissues obtained by surgical biopsy (18 cases of UIP and 29 cases of NSIP). The expression of ligands for CXCR3 [T-H] cells chemoattractant: monokine induced by interferon (IFN)-gamma (MIG), IFN-gamma-inducible protein of 10 kD, and IFN-inducible T cell alpha chemoattractant] and ligands for CCR4 [T(H)2 cells chemoattractant: thymus- and activation-regulated chemokine and macrophage-derived chemokine (MDC)] were analyzed by real-time reverse transcriptase polymerase chain reaction. Results: MIG and IFN gamma-inducible protein of 10 kD expression were significantly higher in NSIP compared with UIP. MDC expression was increased in UIP compared with NSIP, although the difference was not significant. MIG/MDC is significantly elevated in NSIP but not UIP. Interestingly, MIG/MDC was significantly higher in NSIP group 3 (NSIP with extensive fibrosis) compared with UIP. Conclusions: These results may indicate that these 2 diseases have a different pathophysiology. MIG/MDC may be a Useful marker to distinguish these 2 diseases.
  • Takayoshi Fujibayashi, Naozumi Hashimoto, Mayumi Jijiwa, Yoshinori Hasegawa, Toshihisa Kojima, Naoki Ishiguro
    BMC Pulmonary Medicine 9 45 2009年9月16日  査読有り
    Background: To determine whether oral administration of geranylgeranylacetone (GGA), a nontoxic anti-ulcer drug that is an inducer of heat shock protein (HSP) 70, protects against drug-induced lung injury/fibrosis in vivo. Methods: We used a bleomycin (BLM)-induced lung fibrosis model in which mice were treated with oral 600 mg/kg of GGA before and after BLM administration. Inflammation and fibrosis were evaluated by histological scoring, hydroxyproline content in the lung and inflammatory cell count, and quantification by ELISA of macrophage inflammatory protein-2 (MIP-2) in bronchoalveolar lavage fluid. Apoptosis was evaluated by the TUNEL method. The induction of HSP70 in the lung was examined with western blot analysis and its localization was determined by immunohistochemistry. Results: We confirmed the presence of inflammation and fibrosis in the BLM-induced lung injury model and induction of HSP70 by oral administration of GGA. GGA prevented apoptosis of cellular constituents of lung tissue, such as epithelial cells, most likely related to the de novo induction of HSP70 in the lungs. GGA-treated mice also showed less fibrosis of the lungs, associated with the findings of suppression of both production of MIP-2 and inflammatory cell accumulation in the injured lung, compared with vehicle-treated mice. Conclusion: GGA had a protective effect on drug-induced lung injury/fibrosis. Disease-modifying antirheumatic drugs such as methotrexate, which are indispensable for the treatment of rheumatoid arthritis, often cause interstitial lung diseases, an adverse event that currently cannot be prevented. Clinical use of GGA for drug-induced pulmonary fibrosis might be considered in the future. © 2009 Fujibayashi et al licensee BioMed Central Ltd.
  • Yasuyuki Takagi, Naozumi Hashimoto, Sem H. Phan, Kazuyoshi Imaizumi, Masaki Matsuo, Harunori Nakashima, Izumi Hashimoto, Yuta Hayashi, Tsutomu Kawabe, Kaoru Shimokata, Yoshinori Hasegawa
    AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY 297(3) L420-L431 2009年9月  査読有り
    Takagi Y, Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Hashimoto I, Hayashi Y, Kawabe T, Shimokata K, Hasegawa Y. Erythromycin-induced CXCR4 expression on microvascular endothelial cells. Am J Physiol Lung Cell Mol Physiol 297: L420-L431, 2009. First published June 5, 2009; doi: 10.1152/ajplung.90477.2008.-Although stromal-derived factor-1 (SDF-1) via its cognate receptor CXCR4 is assumed to play a critical role in migration of endothelial cells during new vessel formation after tissue injury, CXCR4 expression on endothelial cells is strictly regulated. Erythromycin (EM), a 14-membered ring macrolide, has an anti-inflammatory effect that may account for its clinical benefit in the treatment of chronic inflammatory diseases. However, the effects of EM on endothelial cells and especially their expression of CXCR4 have not been fully evaluated. In this study, we demonstrated that EM markedly induced CXCR4 surface expression on microvascular endothelial cells in vitro and lung capillary endothelial cells in vivo. This ability to induce CXCR4 surface expression on endothelial cells was restricted to 14-membered ring macrolides and was not observed in other antibiotics including a 16-membered ring macrolide, josamycin. Furthermore, this EM-induced expression of CXCR4 on endothelial cells was functionally significant as demonstrated by chemotaxis assays in vitro. These findings suggest that EM-induced CXCR4 surface expression on endothelial cells may promote migration of CXCR4-expressing endothelial cells into sites of tissue injury, which may be associated with the known antiinflammatory activity of this macrolide.
  • Masataka Shibasaki, Tetsuya Yagi, Hiroshi Yatsuya, Masakazu Okamoto, Mitsunori Nishikawa, Hisashi Baba, Naozumi Hashimoto, Kazuyoshi Senda, Tsutomu Kawabe, Kazumitsu Nakashima, Kazuyoshi Imaizumi, Kaoru Shimokata, Yoshinori Hasegawa
    JOURNAL OF INFECTION 58(6) 467-469 2009年6月  査読有り
  • Masataka Shibasaki, Katsunori Hashimoto, Masakazu Okamoto, Yuta Hayashi, Kazuyoshi Imaizumi, Naozumi Hashimoto, Nobuaki Ozaki, Toyoharu Yokoi, Kenzo Takagi, Yoshinori Hasegawa, Kaoru Shimokata, Tsutomu Kawabe
    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 40(5) 536-542 2009年5月  査読有り
    Although Pneumocystis infection might be one of the causes of secondary pulmonary alveolar proteinosis (PAP), the mechanism of its pathogenesis is uncertain. We analyzed a mouse model of secondary PAP resulting from Pneumocystis infection using mice deficient in CD40 (CD40KO), and evaluated the mechanism of the pathogenesis of secondary PAP from the viewpoint of surfactant-associated protein (SP) homeostasis, the overproduction of SP by type II alveolar epithelial cells, and the phagocytic function of alveolar macrophages (AMs). The effect of CD40 on SP production was also investigated in vitro using the H441 cell line, which has a phenotype similar to type II alveolar epithelial cells and primary alveolar epithelial cells. After long-term exposure to ovalbumin, CD40KO mice showed Pneumocystis infection and accumulation of surfactants in the alveoli (ApCD40KO). The amounts of SP production were up-regulated in ApCD40KO mice compared with wildtype mice treated using the same procedure. On the other hand, AMs from ApCD40KO mice did not show either phagocytic dysfunction or down-regulation of PU.1 expression. Furthermore, the stimulation of CD40-CD40 ligand (CD154) pathway regulated the production of SPs in H441 cells or primary alveolar epithelial cells. These results suggested that CD40KO mice could be one of the models useful for developing secondary PAP resulting from Pneumocystis infection. Surfactant accumulation was due to the overproduction in our model of secondary PAP. The CD40-CD154 interaction plays an important role in the regulation of surfactant-associated protein production.
  • Etsuko Hirose, Miyoko Matsushima, Kenzo Takagi, Yui Ota, Keiko Ishigami, Tatsuya Hirayama, Yuta Hayashi, Toshinobu Nakamura, Naozumi Hashimoto, Kazuyoshi Imaizumi, Kenji Baba, Yoshinori Hasegawa, Tsutomu Kawabe
    INFLAMMATION 32(2) 99-108 2009年4月  査読有り
    Kaempferol is one of the most commonly found dietary flavonoids. The exposure to kaempferol is known to inhibit degranulation from mast cells, but the inhibitory mechanism of degranulation has not been clarified yet. In this study, we investigated the involvement of heme oxygenase (HO)-1 in the anti-allergic action of kaempferol against degranulation in rat basophilic leukemia (RBL-2H3) cells. Our results demonstrate upregulation of HO enzymatic activity after short (15 min) exposure to kaempferol, followed by the induction of HO-1 expression in protein. The involvement of HO-1 in the kaempferol-induced inhibition of degranulation was confirmed using tin protoporphyrin IX (SnPP), a HO-1 inhibitor. These findings strongly suggest that kaempferol exerts anti-allergic actions via activation of the HO-1.
  • Y. Shindo, S. Sato, E. Maruyama, T. Ohashi, M. Ogawa, N. Hashimoto, K. Imaizumi, T. Sato, Y. Hasegawa
    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 179(3) 633-640 2009年  査読有り
    BACKGROUND: Health-care-associated pneumonia (HCAP) is a relatively new concept. Epidemiologic studies are limited, and initial empirical antibiotic treatment is still under discussion. This study aimed to reveal the differences in mortality and pathogens between HCAP and community-acquired pneumonia (CAP) in each severity class, and to clarify the strategy for the treatment of HCAP. METHODS: We conducted a retrospective observational study of patients with HCAP and CAP who were hospitalized between November 2005 and January 2007, and compared baseline characteristics, severity, pathogen distribution, antibiotic regimens, and outcomes. In each severity class (mild, moderate, and severe) assessed using the A-DROP scoring system (ie, age, dehydration, respiratory failure, orientation disturbance, and low BP), we investigated the in-hospital mortality and occurrence of potentially drug-resistant (PDR) pathogens. RESULTS: A total of 371 patients (141 HCAP patients, 230 CAP patients) were evaluated. The proportion of patients in the severe class was higher in the HCAP patients than in CAP patients. In the moderate class, the in-hospital mortality proportion of HCAP patients was signific
  • 田村 真理子, 近藤 征史, 堀尾 美穂子, 橋本 直純, 今泉 和良, 久米 裕昭, 山本 雅史, 齋藤 博, 長谷川 好規
    肺癌 48(5) 558-558 2008年10月5日  
  • Atsushi Sumida, Yoshinori Hasegawa, Masakazu Okamoto, Naozumi Hashimoto, Kazuyoshi Imaizumia, Hiroshi Yatsuya, Toyoharu Yokoi, Kenzo Takagi, Kaoru Shimokata, Tsutomu Kawabe
    ARCHIVES OF MEDICAL RESEARCH 39(5) 503-510 2008年7月  査読有り
    Background. Inflammatory response in pulmonary fibrosis closely resembles a T-helper (Th) 2 immune response. For recruitment to an inflammatory lesion, the majority of Th1 cells express CXC chemokine receptor 3, recognizing monokine induced by interferon-gamma (Mig), interferon gamma-inducible protein of 10 kD (IP-10), and interferon-inducible T-cell alpha chemoattractant (I-TAC). Th2 cells express CC chemokine receptor 4, recognizing thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC). We investigated the Th1/Th2 chemokine production patterns by lung fibroblasts and their evaluation in bronchoalveolar lavage (BAL) fluid of interstitial lung disease. Methods. The production pattern of Th1/Th2 chemokines by lung fibroblasts was examined in ELISA and quantitative reverse transcriptase polymerase chain reactions. Th1/ Th2 chemokine levels in BAL fluid of idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP) were examined to evaluate the clinical relevance of Th1/Th2 chemokines. Results. The lung fibroblasts were polarized to produce Th1-type chemokines by the pro-inflammatory cytokine, tumor necrosis factor (TNF)-alpha and the anti-fibrotic cytokine, interferon (IFN)-gamma. However, the induction patterns of chemokines by these two cytokines were different, i.e., involving predominant induction of IP-10 and I-TAC by TNF-alpha and induction of Mig by IFN-gamma. Although Mig, IP-10, and I-TAC were produced within the BAL fluid of patients, TARC and MDC were at significantly low levels. Conclusions. Our results suggest that lung fibroblasts tend to induce a Th1-type immune response under normal conditions, and that a Th2-type immune response does not play a significant role in smoldering inflammation around the established lesions in IPF and NSIP. (c) 2008 IMSS. Published by Elsevier Inc.
  • Matsuno T, Ito Y, Ohashi T, Morise M, Takeda N, Shimokata K, Imaizumi K, Kume H, Hasegawa Y
    J Pharmacol Exp Ther 327 453-464 2008年  査読有り
  • Takahasi K, Hasegawa Y, Abe T, Yamamoto T, Nakashima K, Imaizumi K, Shimokata K
    Tuberculosis 88 52-57 2008年  
  • 橋本 直純, 今泉 和良, 松尾 正樹, 長谷川 好規
    肺癌 47(5) 487-487 2007年10月10日  
    (一般演題(口演)6 分子生物学,第48回日本肺癌学会総会号)
  • 今泉 和良, 橋本 泉, 本多 豊大, 橋本 直純, 近藤 征史, 長谷川 好規, 川部 勤, 下方 薫
    肺癌 47(5) 491-491 2007年10月10日  
    (一般演題(口演)9 癌性胸膜炎・心膜炎,第48回日本肺癌学会総会号)
  • Masakazu Okamoto, Kazuyoshi Imaizumi, Yoshinori Hasegawa, Naozumi Hashimoto, Atsushi Sumida, Masataka Shibazaki, Kenzo Takagi, Kaoru Shimokata, Tsutomu Kawabe
    RESPIROLOGY 12(4) 581-584 2007年7月  査読有り
    Background and objectives: Macrophage-derived chemokine (MDC/CCL22) is recognized as a T-helper (Th) 2-type chemokine. Both malignant and tuberculous pleural effusions are typically lymphocytic pleural effusions. Tuberculous pleural effusions have a more polarized Th1 reaction than malignant effusions, which are predominantly Th2 in nature. The aim of this study was to compare the levels of MDC in malignant pleural effusions with those in tuberculous pleural effusions to help delineate the role of MDC in Th2 versus Th1 effusions. Methods: Forty-three patients with pleural effusions (32 malignant, 11 tuberculous) were studied. The concentration of MDC in the pleural effusion was measured by ELISA. Results: The median concentration of MDC was lower in malignant pleural effusions than in tuberculous pleural effusions (P &lt; 0.005). Conclusions: MDC has been reported to both promote and suppress antitumour immunity. The low concentration of MDC in malignant effusions is likely to minimise its antitumour activity but the precise role of MDC in malignant and tuberculous effusions needs to be investigated further.
  • 今泉 和良, 近藤 征史, 川部 勤, 橋本 直純, 横井 香平, 長谷川 好規, 下方 薫
    肺癌 46(5) 611-611 2006年11月5日  
    (症例6, 第47回日本肺癌学会総会)
  • Toru Nakanishi, Kazuyoshi Imaizumi, Yoshinori Hasegawa, Tsutomu Kawabe, Naozumi Hashimoto, Masakazu Okamoto, Kaoru Shimokata
    CANCER IMMUNOLOGY IMMUNOTHERAPY 55(11) 1320-1329 2006年11月  査読有り
    Background: Ligands for CXCR3 chemokines [IFN-gamma-inducible protein of 10 kD (IP-10/CXCL10), monokine induced by IFN-gamma (Mig/CXCL9), IFN-inducible T cell a chemoattractant (I-TAC/CXCL11)] and those for CCR4 [macrophage-derived chemokine (MDC/CCL22), thymus- and activation-regulated chemokine (TARC/CCL17)] have been shown to play the central roles for T helper-cell recruitment into the tissues. To examine the role of these chemokines in tumor progression of lung cancer, we investigated their expression in human lung cancer tissues to determine the possible relationship between their expression and the prognosis of patients. Methods: Total RNA was prepared from lung cancer tissues of 40 patients ( 24 adenocarcinoma and 16 squamous cell carcinoma). We measured gene expression levels of chemokines (IP-10, Mig, I-TAC, MDC and TARC) by real-time quantitative RT-PCR. Results: Higher gene expression of MDC in lung cancer was significantly correlated with longer disease-free survival time and lower risk of recurrence after tumor resection. We could not find any significant relationship of IP-10, Mig, I-TAC and TARC gene expression with disease-free survival or lower risk of recurrence after surgery. Conclusions: These results suggest that increased gene expression of MDC in tumor tissues may be a predictive marker for improving the prognosis of lung cancer.
  • Naozumi Hashimoto, Kazuyoshi Imaizumi, Toyohiro Honda, Tsutomu Kawabe, Tetsuro Nagasaka, Kaoru Shimokata, Yoshinori Hasegawa
    LUNG CANCER 53(3) 387-390 2006年9月  査読有り
    We report the case of a woman with gefitinib-sensitive lung adenocarcinoma, who was successfully re-treated with gefitinib for carcinomatous meningitis as the disease recurrence. The good response to gefitinib treatment was supported in part by the existence of epidermal growth factor receptor mutation in carcinoma cells in the specimen obtained from transbronchial lung biopsy, in which E709G in exon 18 and L858R in exon 21 were shown. Although carcinomatous meningitis had been well controlled by the treatment with gefitinib, serum carcinoembryonic antigen (CEA) level increased with re-growth of primary tumor and development of lymphangitic carcinomatosis. Immunohistochemical findings revealed de novo emergence of CEA-producing carcinoma cells in the biopsy specimen taken after recurrence of pulmonary lesion during re-treatment of gefitinib, but revealed little or no CEA expression in the specimen obtained at first presentation. These facts may suggest the possibility of oligo clonality of carcinoma cells in this case. (C) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Suzuki R, Hasegawa Y, Baba K, Saka H, Saito H, Taniguchi H, Yamamoto M, Matsumoto S, Kato K, Oishi T, Imaizumi K, Shimokata K
    British Journal of Cancer 94 1599-1603 2006年  
  • Kazuyoshi Imaizumi, Mihoko Sugishita, Miho Usui, Tsutomu Kawabe, Naozumi Hashimoto, Yoshinori Hasegawa
    INTERNAL MEDICINE 45(10) 685-688 2006年  査読有り
    Two patients with rheumatoid arthritis (RA) that developed serious infectious complications following anti-TNF alpha therapy (infliximab) are reported. Patient 1 developed tuberculosis with high fever, refractory diarrhea and mediastinal lymphadenopathy. Trans-bronchial needle biopsy was useful to confirm the diagnosis. Patient 2 showed sudden onset of dyspnea with diffuse bilateral lung infiltration caused by pneumocystis jiroveci pneumonia and the diagnosis was confirmed by broncho-alveolar lavage. Physicians should be alerted to infectious complications with atypical presentation and rapid progression in infliximab-treated patients. Invasive diagnostic procedures including fiber-optic bronchoscopy may be necessary early in the course for such cases.
  • Yoshinori Hasegawa, Yuichi Ando, Maki Ando, Naozumi Hashimoto, Kazuyoshi Imaizumi, Kaoru Shimokata
    INTEGRATED MOLECULAR MEDICINE FOR NEURONAL AND NEOPLASTIC DISORDERS 1086 223-232 2006年  査読有り
    This article focuses on pharmacogenetic associations between genetic polymorphism of uridine diphosphate glucuronosyltransferase (UGT)1A1 gene and irinotecan toxicity. Accumulating evidence provides support to the idea that determination of UGT1A1 polymorphisms before irinotecan treatment is clinically useful and important for predicting and avoiding related toxicities. On the basis of these backgrounds, the irinotecan label was updated in 2005 in the United States to provide pharmacogenetic information, and a dose reduction of irinotecan should be considered for patients known to be homozygous for the UGT1A1*28 allele when administered in combination with other agents or a single agent. The irinotecan/UGT1A1 issue and the development of molecular diagnostic testing are now to be translated into clinical practice.
  • M Okamoto, Y Hasegawa, T Hara, N Hashimoto, K Imaizumi, K Shimokata, T Kawabe
    CHEST 128(6) 4030-4035 2005年12月  査読有り
    Study objectives: Malignant and tuberculous pleurisies are two major causes of lymphocyte-dominant pleurisy. Several studies have already reported that tuberculous pleurisy is a T-helper type 1(Th1)-dominant disease. in this study, we sought to examine the Th1/T-helper type 2 (Th2) balance, especially focusing on the polarizing status of T-cells to Th1/Th2 in malignant pleural effusions by measuring cytokines in pleural effusions and by evaluating the polarizing status of T-cells on the point of stimulation with interleukin (IL)-12 and/or IL-18. Furthermore, we evaluated inhibitors of interferon (IFN)-gamma production in effusions to rule out the possibility of direct inhibition of T-cell polarization. Patients: Effusion samples were collected from 19 patients with malignant pleurisy caused by lung cancer and from 7 patients with tuberculous pleurisy. Measurements: Concentrations of pleural fluid IFN-gamma, IL-12, and IL-4 were measured. IFN-gamma production of T-cells enriched from malignant pleural effusions in the presence of IL-12 and/or IL-18 was also examined. We further compared the inhibitory activity of malignant pleural effusions against IFN-gamma production and analyzed the expression of T-cell immunoglobulin mucin, mucin domain (Tim-3), a Th1-specific molecule in pleural fluid T-cells. Results: Although malignant pleural effusions showed low levels of Tb1 and Th2 cytokines and ratios of IFN-gamma and IL-12 to IL-4 were low, isolated T-cells produced a significant level of IFN-gamma in the presence of IL-12 and IL-18. Soluble factors were not found to inhibit IFN-gamma production in malignant pleural effusions. In tuberculous pleural effusion, ratios of IFN-gamma and IL-12 to IL-4 were significantly higher, and T-cells showed the expression of Tim-3 messenger RNA. Conclusions: We confirmed that T-cells in the malignant pleural effusions are mainly naive or not definitely polarized to Th1. Moreover, malignant tumor does not actively distort the cytokine condition through production of soluble inhibitors within effusions. The present study indicates that antitumor immunity may be enhanced by restored IFN-gamma activity through combination of IL-12 and IL-18, and that it will lead to new therapies for malignant effusion.
  • 今泉 和良, 中西 亨, 川部 勤, 岡本 真和, 伊藤 源士, 橋本 直純, 住田 敦, 小島 克之, 伊藤 康, 久米 裕昭, 関戸 好孝, 長谷川 好規, 下方 薫
    日本呼吸器学会雑誌 43(増刊) 277-277 2005年4月  
  • M Okamoto, T Kawabe, Y Iwasaki, T Hara, N Hashimoto, K Imaizumi, Y Hasegawa, K Shimokata
    JOURNAL OF LABORATORY AND CLINICAL MEDICINE 145(2) 88-93 2005年2月  査読有り
    Tuberculous and malignant pleural effusions are representative of lymphocytic pleural effusions. In tuberculous pleurisy, especially, T-helper type 1 (Th1) cytokines are dominant, containing, for example, high concentrations of interferon (IFN)-gamma. We focused on cytokines that induced expression of IFN-gamma and Th1 cell-specific CXC chemokines induced by IFN-gamma. We also evaluated the diagnostic utility of these markers in tuberculous pleural effusions. Forty-three patients with pleural effusions (I I with tuberculous pleuritis, 32 with malignant pleuritis) were studied. We measured the pleural concentrations of IFN-gamma, IFN-gamma-inducing cytokines (interleukin (IL)-12 and IL-18), and IFN-gamma-inducible chemokines interferon-gamma-inducible protein of 10-kD (IP-10), monokine induced by interferon-gamma (Mig), and interferon-inducible T-cell alpha chemoattractant (I-TAC). Our results demonstrate that the concentrations of IFN-gamma, IFN-gamma-inducing cytokines, and IFN-gamma-inducible chemokines were all higher in tuberculous pleural effusions than in malignant pleural effusions. Also, IFN-gamma was significantly correlated with IL-12, Mig, and I-TAC. Moreover, receiver-operator-characteristic (ROC) analysis demonstrated that IFN-gamma produced a greater area under the ROC curve than any other factor. We conclude that the concentrations of IFN-gamma, cytokines that induced expression of IFN-gamma, and chemokines induced by IFN-gamma in tuberculous pleural effusion were all increased. The Th1 chemokines we examined, especially IP-10, are comparable to IFN-gamma as diagnostic markers of tuberculous and malignant pleural effusions, although IFN-gamma is the most valuable.
  • Kataoka K, Taniguchi H, Hasegawa Y, Kondoh Y, Kimura T, Nishiyama O, Imaizumi K, Kawabe T, Kume H, Shimokata K
    Respiratory Medicine 100 698-704 2005年  
  • Ando M, Saka H, Ando Y, Minami H, Kuzuya T, Yamamoto M, Watanabe A, Sakai S, Shimokata K, Hasegawa Y
    Cancer Chemotherapy and Pharmacology 55(6) 552-558-8 2005年  
  • B Hu, Z Wu, H Jin, N Hashimoto, TJ Liu, SH Phan
    JOURNAL OF IMMUNOLOGY 173(7) 4661-4668 2004年10月  査読有り
    The role of IL-1beta in inflammation is amply documented, but its ability to inhibit myofibroblast differentiation and, in particular, the suppression of alpha-smooth muscle actin (alpha-SMA) gene expression is less well understood. Because IL-1beta can induce C/EBPbeta expression, the role of C/EBPbeta isoforms in IL-1beta regulation of a-SMA gene expression was investigated in rat lung myofibroblasts. The results showed that IL-1beta inhibited alpha-SMA expression in a dose-dependent manner, which was associated with stimulation of the expression of both C/EBPbeta isoforms, liver-enriched activating protein (LAP) and liver-enriched inhibitory protein (LIP). However, a greater increase in LIP relative to LAP expression resulted in a reduced LAP/LIP ratio after IL-1beta treatment. Transfection with an LAP-expressing plasmid stimulated, whereas an LIP-expressing plasmid inhibited, a-SMA expression. Cells from C/EBPbeta-deficient mice had reduced levels of a-SMA expression and promoter activity, which failed to respond to IL-1beta treatment. Sequence analysis identified the presence of a C/EBPbeta consensus binding sequence in the a-SMA promoter, which, when mutated, resulted in diminished promoter activity and abolished its responsiveness to IL-1beta treatment. EMSA revealed binding of C/EBPbeta to this C/EBP,6 consensus binding sequence from the a-SMA promoter. Finally, IL-1beta enhanced the expression of eukaryotic initiation factor 4E, a stimulator of LIP expression, which may account for a mechanism by which IL-1beta could alter the LAP/LIP ratio. These data taken together suggest that C/EBPbeta isoforms regulate alpha-SMA gene expression, and that its inhibition by IL-1beta was due to preferential stimulation of LIP expression.
  • TJ Liu, H Jin, M Ullenbruch, B Hu, N Hashimoto, B Moore, A McKenzie, NW Lukacs, SH Phan
    JOURNAL OF IMMUNOLOGY 173(5) 3425-3431 2004年9月  査読有り
    Found in inflammatory zone (FIZZ)l, also known as resistin-like molecule a, belongs to a novel class of cysteine-rich secreted protein family, named FIZZ/resistin-like molecule, with unique tissue expression patterns. FIZZ1 is induced in alveolar type 11 epithelial cells (AECs) in bleomycin (BLM)-induced lung fibrosis, and found to induce myofibroblast differentiation in vitro. The objective of this study was to elucidate the regulation of AEC FIZZ1 expression in pulmonary fibrosis. AECs were isolated from rat lungs and the effects of a number of cytokines on FIZZ1 expression were evaluated by RT-PCR. Of all cytokines examined, only IL-4 and IL-13 were effective in stimulating FIZZ1 expression in AECs. Stimulation by IL-4/11L-13 was accompanied by increases in phosphorylated STAT6 and JAK1. FIZZ1 expression was also stimulated by transfection with a STAT6 expression plasmid, but was inhibited by antisense oligonucleotides directed against STAT6. In vivo studies showed that compared with wild-type controls, both IL-4- and IL-13-deficient mice showed reduced BLM-induced lung FIZZ1 expression and fibrosis, which were essentially abolished in IL-4 and IL-13 doubly deficient mice. Furthermore, STAT6-deficient mice showed marked reduction in BLM-induced lung FIZZ1 expression. Thus, IL-4 and IL-13 are potent inducers of AEC FIZZ1 expression via STAT6 and play key roles in BLM-induced lung FIZZ1 expression and fibrosis. This represents a potential mechanism by which IL-4/IL-43 could play a role in the pathogenesis of lung fibrosis.
  • N Hashimoto, T Kawabe, K Imaizumi, T Hara, M Okamoto, K Kojima, K Shimokata, Y Hasegawa
    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 30(6) 808-815 2004年6月  査読有り
    Activated alveolar macrophages (AMphi) are known to constitute a critical modulator of the lung inflammatory response through the production of various mediators. However, the role of activated AMphi in acute lung injury (ALI) and acute respiratory, distress syndrome is less well known. To address this issue, we examined a lipopolysaccharide (LPS)-induced lung injury model for the role of activated AMphi in vivo, focusing on activation through CD40, which is one of the most important pathways for the activation of antigen-presenting cells. Without CD40, LPS-induced ALI was significantly reduced in its histological degree of injury and recruitment of neutrophils into the lung. In addition, the release in the lung of inflammatory mediators such as tumor necrosis factor-alpha, interleukin-1beta, macrophage inflammatory protein 2, or matrix metalloproteinase was significantly reduced in mice deficient in CD40 (CD40KO). To elucidate the mechanism of this attenuation of ALI in CD40KO mice, we studied the function of AMphi ex vivo. AMphi purified from CD40KO mice could not induce expression of inducible nitric oxide synthase (NOS) by LPS, although iNOS in wild-type AMphi was induced by LIPS independently of CD40-CD154 interaction. The loss of surface expression of CD40 was enough to interrupt the expression of NOS in AMphi in response to LPS. Also based on the tissue nitrotyrosine staining, the reactive oxygen and nitrogen intermediates seemed to be reduced in tissue in CD40KO mice. These results indicated that activation of AMphi through CD40 might be involved not only in amplification by the interaction with CD154 but also in the development of ALI by CD40 itself, and that the functional blockade of CD40 would yield one of the targets for the treatment of LPS-induced ALI and acute respiratory distress syndrome.
  • Sato, M, Okamoto, M, Takagi, Y, Ikeda, T, Niimi, T, Fukatsu, E, Maruyama, K, Nara, Y, Shimokata, K, Hasegawa, Y
    Intern Med 43(2) 117-9-119 2004年  査読有り
    We report a 74-year-old woman with cervical cancer who developed pulmonary cryptococcosis which presented as a solitary focal ground-glass opacity (GGO) on high-resolution computed tomography (HRCT). Serial HRCT showed the progression from the GGO to a discrete solid nodule. We hypothesize that the initial GGO may correspond pathologically to partial filling of air spaces with cryptococcal organisms and inflammatory cells. To our knowledge, this is the first report of pulmonary cryptococcosis with a solitary focal GGO on HRCT in the literature.
  • N Hashimoto, H Jin, TJ Liu, SW Chensue, SH Phan
    JOURNAL OF CLINICAL INVESTIGATION 113(2) 243-252 2004年1月  査読有り
    The origin of fibroblasts in pulmonary fibrosis is assumed to be intrapulmonary, but their extrapulmonary origin and especially derivation from bone marrow (BM) progenitor cells has not been ruled out. To examine this possibility directly, adult mice were durably engrafted with BM isolated from transgenic mice expressing enhanced GFP. Induction of pulmonary fibrosis in such chimera mice by endotracheal bleomycin (BLM) injection caused large numbers of GFP(+) cells to appear in active fibrotic lesions, while only a few GFP(+) cells could be identified in control lungs. Flow-cytometric analysis of lung cells confirmed the BLM-induced increase in GFP(+) cells in chimera mice and revealed a significant increase in GFP(+) cells that also express type I collagen. GFP(+) lung Fibroblasts isolated from chimera mice expressed collagen and telomerase reverse transcriptase but not alpha-smooth muscle actin. Treatment of isolated GFP(+) fibroblasts with TGF-beta failed to induce myofibroblast differentiation. Cultured lung fibroblasts expressed the chemokine receptors CXCR4 and CCR7 and responded chemotactically to their cognate ligands, stromal cell-derived factor-1alpha and secondary lymphoid chemokine, respectively. Thus the collagen-producing lung fibroblasts in pulmonary fibrosis can also be derived from BM progenitor cells.

講演・口頭発表等

 9

担当経験のある科目(授業)

 4

共同研究・競争的資金等の研究課題

 14

社会貢献活動

 1