Takeo Iwasaki

Publications (13)46.62 Total impact

• Article: Deletion of tetraspanin CD9 diminishes lymphangiogenesis in vivo and in vitro.

  Takeo Iwasaki, Yoshito Takeda, Kazuichi Maruyama, Yasuyuki Yokosaki, Kazuyuki Tsujino, Satoshi Tetsumoto, Hanako Kuhara, Kaori Nakanishi, Yasushi Otani, Yingji Jin, [......], Ryo Takahashi, Mayumi Suzuki, Koji Inoue, Izumi Nagatomo, Sho Goya, Takashi Kijima, Toru Kumagai, Isao Tachibana, Ichiro Kawase, Atsushi Kumanogoh
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  ABSTRACT: Tetraspanins have emerged as key players in malignancy and inflammatory diseases, yet little is known about their roles in angiogenesis, and nothing about their involvement in lymphangiogenesis. We here found that tetraspanins are abundantly expressed in human lymphatic endothelial cells (LEC) and tumor LECs. After intrathoracic tumor implantation, metastasis to lymph nodes was diminished and accompanied by decreased angiogenesis and lymphangiogenesis in tetraspanin CD9 Knockout (KO) mice. Moreover, lymphangiomas induced in CD9-KO mice were less pronounced with decreased lymphangiogenesis when compared with wild-type mice. While mouse LEC isolated from CD9-KO mice showed normal adhesion, lymphangiogenesis was markedly impaired in several assays (migration, proliferation, and cable formation) in vitro, and in the lymphatic ring assay ex vivo. Consistent with these findings in mouse LEC, knocking down of CD9 in human LEC also showed decreased migration, proliferation, and cable formation. Immunoprecipitation analysis demonstrated that deletion of CD9 in LEC diminished functional complexes between vascular endothelial growth factor receptor (VEGFR)-3, and integrins (α5 and α9). Therefore, knocking down of CD9 in LEC attenuated VEGFR-3 signaling as well as down-stream signaling such as Erk, and p38 upon VEGF-C stimulation. Finally, double-deletion of CD9/CD81 in mice exhibited abnormal development of lymphatic vasculature in the trachea and diaphragm, suggesting that CD9 and a closely related tetraspanin CD81 coordinately play an essential role in physiological lymphangiogenesis. In conclusion, tetraspanin CD9 modulate molecular organization of integrins in LEC, thereby supporting several functions required for lymphangiogenesis.
  Journal of Biological Chemistry 12/2012; · 4.77 Impact Factor
• Article: Tetraspanin CD151 protects against pulmonary fibrosis by maintaining epithelial integrity.

  Kazuyuki Tsujino, Yoshito Takeda, Toru Arai, Yasushi Shintani, Ryosaku Inagaki, Hiroyuki Saiga, Takeo Iwasaki, Satoshi Tetsumoto, Yingji Jin, Shoichi Ihara, [......], Hiroshi Kida, Takashi Kijima, Mari Ito, Masanori Kitaichi, Yoshikazu Inoue, Isao Tachibana, Kiyoshi Takeda, Meinoshin Okumura, Martin E Hemler, Atsushi Kumanogoh
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  ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology with few treatment options. Although tetraspanins are involved in various diseases, their roles in fibrosis have not been determined. Objectives: To investigate the role of tetraspanin CD151 in pulmonary fibrosis. CD151 knockout (KO) mice were studied by histological, biochemical, and physiological analyses and compared with wild-type mice and CD9 KO mice. Further mechanistic analyses were performed in vitro, in vivo, and on samples from patients with IPF. A microarray study identified an enrichment of genes involved in connective tissue disorders in the lungs of CD151 KO mice, but not in CD9 KO mice. Consistent with this, CD151 KO mice spontaneously exhibited age-related pulmonary fibrosis. Deletion of CD151 did not affect pulmonary fibroblast functions but instead degraded epithelial integrity via attenuated adhesion strength on the basement membrane; CD151-deleted alveolar epithelial cells exhibited increased α-SMA expression with activation of p-Smad2, leading to fibrotic changes in the lungs. This loss of epithelial integrity in CD151 KO lungs was further exacerbated by intratracheal bleomycin exposure, resulting in severe fibrosis with increased mortality. We also observed decreased numbers of CD151-positive alveolar epithelial cells in patients with IPF. CD151 is essential for normal function of alveolar epithelial cells; loss of CD151 causes pulmonary fibrosis as a result of epithelial disintegrity. Given that CD151 may protect against fibrosis, this protein represents a novel target for the treatment of fibrotic diseases.
  American Journal of Respiratory and Critical Care Medicine 05/2012; 186(2):170-80. · 11.08 Impact Factor
• Article: Involvement of endothelial apoptosis underlying chronic obstructive pulmonary disease-like phenotype in adiponectin-null mice: implications for therapy.

  Kaori Nakanishi, Yoshito Takeda, Satoshi Tetsumoto, Takeo Iwasaki, Kazuyuki Tsujino, Hanako Kuhara, Yingji Jin, Izumi Nagatomo, Hiroshi Kida, Sho Goya, Takashi Kijima, Norikazu Maeda, Tohru Funahashi, Iichiro Shimomura, Isao Tachibana, Ichiro Kawase
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  ABSTRACT: Chronic obstructive pulmonary disease is frequently complicated with comorbidities, such as cardiovascular disease, osteoporosis, and body weight loss, but the causal link remains unclear. To investigate the role of adiponectin in the pathogenesis of chronic obstructive pulmonary disease and its potential use in therapy. Adiponectin localization and dynamics in the lung were analyzed in an elastase-induced emphysema model. Next, the lung of adiponectin-knockout mice, extrapulmonary effects, and the underlying mechanism were investigated. Finally, we tested whether exogenous adiponectin could ameliorate the emphysematous change in adiponectin-knockout mice. Adiponectin expression in lung vasculature and plasma concentration of adiponectin were reduced after elastase-instillation. Notably, adiponectin-knockout mice showed progressive alveolar enlargement and increased lung compliance. They further exhibited not only systemic inflammation, but also extrapulmonary phenotype, such as body weight loss, fat atrophy, and osteoporosis. Moreover, endothelial apoptosis was enhanced in the lungs of adiponectin-knockout mice, as evidenced by caspase-3 activity. Consistent with this, expressions of vascular endothelial growth factor receptor-2 and platelet endothelial cell adhesion molecule-1 on endothelial cells were decreased in the adiponectin-knockout mice. Finally, adenovirus-mediated adiponectin supplementation ameliorated the emphysematous phenotype. Adiponectin-knockout mice develop progressive chronic obstructive pulmonary disease-like phenotype with systemic inflammation and extrapulmonary phenotypes. Hypoadiponectinemia could thus play a critical role in the progression of chronic obstructive pulmonary disease and concomitant comorbidities through endothelial dysfunction. Together, adiponectin could be a novel target for chronic obstructive pulmonary disease therapy.
  American Journal of Respiratory and Critical Care Medicine 01/2011; 183(9):1164-75. · 11.08 Impact Factor
• Article: A 61-year-old man with a lung nodule and elevated serum IgG.

  Takeo Iwasaki, Isao Tachibana, Shigeyuki Yoshida, Kohki Shimazu, Yutaka Takeda, Hiroaki Nagano, Ichiro Kawase
  Chest 05/2010; 137(5):1232-5. · 5.25 Impact Factor
• Article: Tetraspanin CD9 negatively regulates lipopolysaccharide-induced macrophage activation and lung inflammation.

  Mayumi Suzuki, Isao Tachibana, Yoshito Takeda, Ping He, Seigo Minami, Takeo Iwasaki, Hiroshi Kida, Sho Goya, Takashi Kijima, Mitsuhiro Yoshida, Toru Kumagai, Tadashi Osaki, Ichiro Kawase
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  ABSTRACT: Tetraspanins facilitate the formation of multiple molecular complexes at specialized membrane microdomains and regulate cell activation and motility. In the present study, the role of tetraspanin CD9 in LPS-induced macrophage activation and lung inflammation was investigated in vitro and in vivo. When CD9 function was ablated with mAb treatment, small interfering RNA transfection, or gene knockout in RAW264.7 cells or bone marrow-derived macrophages, these macrophages produced larger amounts of TNF-alpha, matrix metalloproteinase-2, and -9 upon stimulation with LPS in vitro, when compared with control cells. Sucrose gradient analysis revealed that CD9 partly colocalized with the LPS-induced signaling mediator, CD14, at low-density light membrane fractions. In CD9 knockout macrophages, CD14 expression, CD14 and TLR4 localization into the lipid raft, and their complex formation were increased whereas IkappaBalpha expression was decreased when compared with wild-type cells, suggesting that CD9 prevents the formation of LPS receptor complex. Finally, deletion of CD9 in mice enhanced macrophage infiltration and TNF-alpha production in the lung after intranasal administration of LPS in vivo, when compared with wild-type mice. These results suggest that macrophage CD9 negatively regulates LPS response at lipid-enriched membrane microdomains.
  The Journal of Immunology 06/2009; 182(10):6485-93. · 5.79 Impact Factor
• Article: Double deficiency of tetraspanins CD9 and CD81 alters cell motility and protease production of macrophages and causes chronic obstructive pulmonary disease-like phenotype in mice.

  Yoshito Takeda, Ping He, Isao Tachibana, Bo Zhou, Kenji Miyado, Hideshi Kaneko, Mayumi Suzuki, Seigo Minami, Takeo Iwasaki, Sho Goya, Takashi Kijima, Toru Kumagai, Mitsuhiro Yoshida, Tadashi Osaki, Toshihisa Komori, Eisuke Mekada, Ichiro Kawase
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  ABSTRACT: CD9 and CD81 are closely related tetraspanins that regulate cell motility and signaling by facilitating the organization of multimolecular membrane complexes, including integrins. We show that CD9 and CD81 are down-regulated in smoking-related inflammatory response of a macrophage line, RAW264.7. When functions of CD9 and CD81 were ablated with monoclonal antibody treatment, small interfering RNA transfection, or gene knock-out, macrophages were less motile and produced larger amounts of matrix metalloproteinase (MMP)-2 and MMP-9 than control cells in vitro. In line with this, CD9/CD81 double-knock-out mice spontaneously developed pulmonary emphysema, a major pathological component of chronic obstructive pulmonary disease (COPD). The mutant lung contained an increased number of alveolar macrophages with elevated activities of MMP-2 and MMP-9 and progressively displayed enlarged airspace and disruption of elastic fibers in the alveoli. Secretory cell metaplasia, a finding similar to goblet cell metaplasia in cigarette smokers, was also observed in the epithelium of terminal bronchioles. With aging, the double-knockout mice showed extrapulmonary phenotypes, including weight loss, kyphosis, and osteopenia. These results suggest that the tetraspanins CD9 and CD81 regulate cell motility and protease production of macrophages and that their dysfunction may underlie the progression of COPD.
  Journal of Biological Chemistry 08/2008; 283(38):26089-97. · 4.77 Impact Factor
• Article: [A case of lung adenocarcinoma effectively treated with sivelestat and corcicosteroid for drug-induced lung disease due to gefitinib].

  Masahide Mori, Takeo Iwasaki, Yukie Nakazawa, Yoshinobu Namba, Manabu Niinaka, Yukihiro Yano, Seigo Kitada, Hiromi Kimura, Nobuyuki Naka, Tatsuya Okada, Masaru Nakagawa, Ryoji Maekura, Soichiro Yokota
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  ABSTRACT: A 70-year-old Japanese man was re-admitted because of relapse of adenocarcinoma of the lung. He received daily administration of gefitinib as second-line chemotherapy. He was given a diagnosis of drug-induced lung disease due to gefitinib on day 6 because of hypoxemia and ground glass opacities in the bilateral lung fields. There was no response to corticosteroid pulse therapy. Continuous administration of sivelestat was intravenously added from day 9. Although mechanical ventilation was required for 10 days, lung infiltrates and hypoxia gradually improved. Sivelestat and corcicosteroid was apparently effective in this case and may be useful treatment for drug-induced lung disease due to gefitinib.
  Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 04/2008; 46(3):232-6.
• Article: [A case of spontaneous resolution of sarcoidosis with primary pulmonary cavitations].

  Takeo Iwasaki, Masahide Mori, Seigo Kitada, Kenji Fushitani, Masaharu Motone, Yoshinobu Namba, Kenji Yosimura, Manabu Niinaka, Mari Miki, Keisuke Miki, Nobuyuki Naka, Toru Hiraga, Masami Ito, Soichiro Yokota, Ryoji Maekura
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  ABSTRACT: On routine physical checkup, a 27-year-old man with productive cough was found to have multiple nodules with cavitation in the bilateral lung fields and mediastinal and hilar lymph adenopathy on chest X-ray film and CT scan. Serum levels of angiotensin converting enzyme and lysozyme were high. Tuberculin reaction was negative. Non-caseous epitheloid granulomas were confirmed in the bronchial wall specimens obtained by trans-bronchial biopsy. The number of lymphocytes and the CD4/CD8 ratio of lymphocytes in bronchoalveolar lavage fluid was increased. Therefore, pulmonary sarcoidosis was diagnosed, and the lung nodules with cavitation were considered due to sarcoidosis. The walls of the cavitations gradually thinned and had almost completely vanished after 6 months of careful observation without steroid therapy.
  Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 02/2007; 45(1):59-64.
• Article: [Case of lung cancer with chylothorax].

  Takeo Iwasaki, Masahide Mori, Yoshinobu Namba, Manabu Niinaka, Hiromi Kimura, Nobuyuki Naka, Tatsuya Okada, Masaru Nakagawa, Soichiro Yokota, Masami Ito
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  ABSTRACT: A 42-year-old man had swelling in the right side of the neck, cough and chest pain. On admission, an abnormal shadow was detected in the right upper lung field and squamous cell carcinoma of the lung with superior vena cava (SVC) syndrome was diagnosed. Concurrent radiotherapy and systemic chemotherapy consisting of cisplatin and vinorelbine induced a partial response. At 15 months after diagnosis, he was re-admitted because of bilateral pleural effusion and facial edema due to relapse of SVC syndrome. Examination of the milky right pleural effusion revealed chylothorax (959mg/dl of beta-lipoprotein and 675mg/dl of triglyceride). The right effusion was finally controlled by pleurodesis with OK-432. Non-traumatic chylothorax is a rare complication of lung cancer.
  Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 11/2006; 44(10):706-10.
• Article: [A case of pneumonitis suspected to be induced by Oseltamivir].

  Yoshinobu Namba, Seigo Kitada, Masahide Mori, Takeo Iwasaki, Masaharu Motone, Manabu Niinaka, Kenji Yoshimura, Mari Miki, Keisuke Miki, Nobuyuki Naka, Toru Hiraga, Ryoji Maekura, Masami Ito
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  ABSTRACT: A 33-year-old man had a high fever and was given Cefcapene and Oseltamivir without a definite diagnosis of influenza. Three days later an abnormal chest shadow was pointed out. Chest CT revealed ground-glass opacities and air-space consolidation in bilateral lung fields. Although he was given antibiotics, lung infiltrates increased and his symptoms worsened. Therefore, he was transferred to our hospital. Corticosteroid pulse-therapy resulted in prompt improvement of chest infiltrates and his symptoms. The drug-induced lymphocyte stimulating test results indicated 170% of oseltamivir and 150% of cefcapene. Considering the clinical course and laboratory data, this was probably drug-induced lung injury caused by oseltamivir.
  Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 06/2006; 44(5):410-4.
• Article: [A case of lung cancer with cranial neuropathy as the first sign of onset due to metastatic leptomeningeal carcinomatosis].

  Takeo Iwasaki, Tatsuya Okada, Yoshinobu Namba, Manabu Niinaka, Yoshito Takeda, Hiromi Kimura, Yoshinobu Naka, Masahide Mori, Masaru Nakagawa, Soichiro Yokota, Masami Ito
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  ABSTRACT: A 68-year-old man suffered right facial palsy and left deafness, however, his condition was considered to be idiopathic and he was followed. Three months later, bloody sputum and hoarseness caused him to be admitted to our hospital. An abnormal shadow was detected in the right upper lung field and adenocarcinoma of the lung with multiple brain metastases was diagnosed. He underwent gamma-knife radiosurgery for the brain lesions and subsequent systemic chemotherapy consisting of combined carboplatin and paclitaxel, which were not effective. Subsequently various neurological symptoms appeared, such as muscle weakness of the extremities, dizziness, and gait disturbance. Adenocarcinoma cells confirmed in the cerebrospinal fluid were similar to those in the obtained by transbronchial curetting. Whole-brain irradiation was performed, however, the neurological symptoms worsened and he died. Leptomeningeal carcinomatosis is difficult to diagnose while the patient is alive. It is thought that cranial neuropathy due to leptomeningeal carcinomatosis is a rare form of onset for lung cancer.
  Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 12/2005; 43(11):664-7.
• Article: Simultaneous bilateral spontaneous pneumothorax observed during the administration of gefitinib for lung adenocarcinoma with multiple lung metastases.

  Masahide Mori, Masaru Nakagawa, Takeya Fujikawa, Takeo Iwasaki, Tomoko Kawamura, Yoshinobu Namba, Manabu Niinaka, Yoshito Takeda, Hiromi Kimura, Nobuyuki Naka, Tatsuya Okada, Toshihiko Yamaguchi, Soichiro Yokota, Masami Ito
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  ABSTRACT: A 41-year-old man with productive cough was admitted to our hospital. His chest roentgenogram showed multiple small nodules in the bilateral lung fields. The nodules were revealed as intrapulmonary metastases of the adenocarcinoma of the lung. Systemic chemotherapy with paclitaxel and carboplatin was not effective, and continuous oral gefitinib therapy was initiated. Twenty-one days later, spontaneous pneumothorax was found in the left lung, and four days after that, in the right lung as well. The extent of the pneumothorax was slight; therefore, he recovered without drainage within several days. Spontaneous pneumothorax, especially bilateral pneumothorax, is a rare complication of chemotherapy for lung cancer.
  Internal Medicine 09/2005; 44(8):862-4. · 0.94 Impact Factor
• Article: Gefitinib in patients with brain metastases from non-small-cell lung cancer: review of 15 clinical cases.

  Yoshinobu Namba, Takashi Kijima, Soichiro Yokota, Manabu Niinaka, Satolo Kawamura, Takeo Iwasaki, Yoshito Takeda, Hiromi Kimura, Tatsuya Okada, Toshihiko Yamaguchi, Masaru Nakagawa, Yoshimoto Okumura, Hajime Maeda, Masami Ito
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  ABSTRACT: The clinical efficacy of gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), on brain metastases (BMs) from non-small-cell lung cancer (NSCLC) was evaluated. Fifteen patients with recurrent NSCLC with metastasis to the brain were treated with gefitinib. The objective tumor response rate (60%; 9 of 15 patients) for BM was the same as for primary tumors. The median time to response of BM was 26 days. In 8 of 9 patients who exhibited partial response in the thoracic lesion, BM showed dramatic regression, including 1 complete response. One patient with stable primary tumor also exhibited partial response in BM with this monotherapy. Brain metastasis-related neurologic symptoms such as hemiparesis, dysarthria, dysphagia, and vertigo improved or disappeared with the objective response of BM as confirmed by magnetic resonance imaging. Central nervous system toxicities were not observed during the treatment. Four of the 9 BM responders are still under treatment with neither adverse events nor disease progression. Two discontinued the treatment because of severe hepatic toxicity and 3 died because of acquired resistance in pulmonary lesions, even though partial response was observed in the BMs. Finally, median duration of response of BM was 8.7 months and median overall survival was 8.3 months (range, 1.8 to > 15.7 months). Molecular targeted therapy against EGFR could be an option for the treatment of BM from NSCLC refractory to conventional chemotherapy plus radiation therapy because it has demonstrated a distinct therapeutic potential against BM compared with primary lung tumor and extracranial metastases.
  Clinical Lung Cancer 10/2004; 6(2):123-8. · 2.94 Impact Factor