Toshihiro Nukiwa

Publications (123)734.33 Total impact

• Article: Interstitial Lung Disease Associated with Gefitinib in Japanese Patients with EGFR-mutated Non-small-cell Lung Cancer: Combined Analysis of Two Phase III Trials (NEJ 002 and WJTOG 3405).

  Hiroaki Akamatsu, Akira Inoue, Tetsuya Mitsudomi, Kunihiko Kobayashi, Kazuhiko Nakagawa, Keita Mori, Toshihiro Nukiwa, Yoichi Nakanishi, Nobuyuki Yamamoto
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  ABSTRACT: OBJECTIVE: Interstitial lung disease associated with gefitinib is a critical adverse reaction. When geftinib was administered to EGFR-unknown patients, the interstitial lung disease incidence rate was approximately 3-4% in Japan, and usually occurs during the first 4 weeks of treatment. However, it has not been fully investigated in EGFR-mutated patients. METHODS: We collected clinical records of participants of two Phase III trials (WJTOG 3405 and NEJ 002), which compared gefitinib with platinum doublet chemotherapy. All patients were EGFR mutated, chemo-naïve and had good performance status. RESULTS: A total of 402 patients were enrolled in this study. In the gefitinib arm, 10 (5.0%) of 201 patients developed interstitial lung disease, of whom five (2.5%) were Grade 3 or greater, with two deaths (1.0%). In contrast, only one patient developed interstitial lung disease (Grade 1) in the chemotherapy arm. With regard to gefitinib, smoking history was significantly associated with developing interstitial lung disease (odds ratio 0.18; 95% confidence interval: 0.05-0.74; P = 0.01). The cumulative incidence rate of interstitial lung disease was similar in the 0-4, 5-8 and 9-12 week time periods. However, between smokers and never-smokers, cumulative incidence rates in the first 4 weeks were significantly different (4.7% versus 0%, P = 0.03). Three of 10 patients developed interstitial lung disease after 8 weeks of gefitinib administration (days 135, 171 and 190, respectively). CONCLUSIONS: Among EGFR-mutated patients, the incidence of interstitial lung disease associated with gefitinib was not different from that in previous reports. Smoking history was associated with developing interstitial lung disease, and smokers had a higher incidence rate of interstitial lung disease in the first 4 weeks.
  Japanese Journal of Clinical Oncology 04/2013; · 1.78 Impact Factor
• Article: A phase II study of irinotecan as a third- or fourth-line treatment for advanced non-small cell lung cancer: NJLCG0703.

  Nobumichi Matsubara, Makoto Maemondo, Akira Inoue, Osamu Ishimoto, Kana Watanabe, Tomohiro Sakakibara, Tatsuro Fukuhara, Naoto Morikawa, Masashi Tanaka, Shunichi Sugawara, Toshihiro Nukiwa
  [show abstract] [hide abstract]
  ABSTRACT: We aimed to evaluate the efficacy and safety of irinotecan monotherapy as a third- or fourth-line treatment for advanced non-small cell lung cancer (NSCLC) patients. Patients with advanced NSCLC refractory to 2 or more previous regimens were treated with 80mg/m(2) irinotecan on days 1, 8, and 15, every 4 weeks. The primary endpoint was the overall response rate (ORR), whereas secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity profiles. From December 2007 to April 2009, 32 patients (median age, 60 years) were enrolled. Most of the patients (75.0%) were male, and 18.8% had a performance status of 2. Six partial responses to irinotecan monotherapy were observed (ORR, 18.8%: 95% confidence interval, 5.3%-32.3%). The disease control rate (DCR) was 78.1%, median PFS was 4.0 months, and median survival time (MST) was 10.4 months. Grade 3-4 neutropenia was observed in 22% of patients, but other toxic effects were moderate. No cases of grade 3-4 diarrhea or treatment-related death were noted. Of the 15 patients for whom progressive disease represented the best response to previous treatment regimens, 2 exhibited a partial response and 9 showed stable disease after irinotecan monotherapy, with a DCR of 73.3%, median PFS of 4.4 months, and MST of 8.2 months. Irinotecan monotherapy is effective for advanced NSCLC patients who have previously failed 2 or more treatment regimens.
  Respiratory investigation. 03/2013; 51(1):28-34.
• Article: Fatal acute interstitial pneumonia in a worker making chips from wooden debris generated by the Great East Japan earthquake and tsunami.

  Shinya Ohkouchi, Masahito Ebina, Katsuhiko Kamei, Hiroshi Moriyama, Tokiwa Tamai, Risa Shibuya, Masakazu Ichinose, Toshihiro Nukiwa
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  ABSTRACT: A man was admitted to our hospital with shortness of breath. He was involved in making wood chips from contaminated debris created by the tsunami that occurred after the Great East Japan Earthquake. Fungi detected at his home and workplace were possible inducers of hypersensitivity pneumonitis, but the absence of precipitating antibodies countered this diagnosis. His rapid and progressive clinical course and surgical lung biopsy and bronchoalveolar lavage findings suggested acute interstitial pneumonia. Electron probe X-ray microanalysis revealed the deposition of excessive exogenous substances in bronchiolar regions. Inhalation of harmful materials was suspected to be the cause of acute lung injury.
  Respiratory investigation. 12/2012; 50(4):129-34.
• Source

  Available from: Toshiki Yabe-Wada

  Article: Regulation of plasmacytoid dendritic cell responses by PIR-B.

  Yoshiya Mitsuhashi, Akira Nakamura, Shota Endo, Kazuya Takeda, Toshiki Yabe-Wada, Toshihiro Nukiwa, Toshiyuki Takai
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  ABSTRACT: Plasmacytoid dendritic cells (PDCs) produce type I interferons (IFNs) in response to viral nucleic acids to exert antiviral immunity. However, PDCs are related to the progress and severity of autoimmune diseases, such as systemic lupus erythematosus, because they respond to host DNA. Therefore, the regulation of PDC activation is critical for maintaining adequate immune responses. Here we show that an inhibitory major histocompatibility complex class I receptor, paired immunoglobulin-like receptor B (PIR-B), suppressed Fms-like tyrosine kinase 3 ligand-induced PDC differentiation in BM cells, as well as Toll-like receptor 9-mediated IFN-α production by PDCs, through the dephosphorylation of STAT1/STAT2. In particular, PIR-B inhibited IFN-α-mediated STAT phosphorylation, suggesting that PIR-B negatively regulates the positive feedback mechanism of IFN-α secretion triggered by Toll-like receptor 9. These results demonstrate a novel regulatory role for PIR-B in PDCs.
  Blood 09/2012; 120(16):3256-9. · 9.90 Impact Factor
• Article: First-line gefitinib in patients aged 75 or older with advanced non-small cell lung cancer harboring epidermal growth factor receptor mutations: NEJ 003 study.

  Makoto Maemondo, Yuji Minegishi, Akira Inoue, Kunihiko Kobayashi, Masao Harada, Shoji Okinaga, Naoto Morikawa, Satoshi Oizumi, Tomoaki Tanaka, Hiroshi Isobe, Shoji Kudoh, Koichi Hagiwara, Toshihiro Nukiwa, Akihiko Gemmah
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  ABSTRACT: Recent studies have demonstrated that first-line treatment with gefitinib, an epidermal growth factor receptor (EFGR)-targeted tyrosine kinase inhibitor, is significantly superior to standard chemotherapy for advanced non-small-cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Meanwhile, the efficacy of gefitinib therapy among elderly populations diagnosed with EGFR-mutated NSCLC has not yet been elucidated. The purpose of this study was to investigate the efficacy and feasibility of gefitinib for chemotherapy-naive patients aged 75 or older with NSCLC harboring EGFR mutations; generally, these patients have no indication for treatment with platinum doublets. Chemotherapy-naive patients aged 75 years or older with performance status 0 to 1 and advanced NSCLC harboring EGFR mutations, as determined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, were enrolled. The enrolled patients received 250 mg/day of gefitinib orally. Between January 2008 and May 2009, 31 patients were enrolled, all of whom were eligible. The median age was 80 (range, 75-87) years. Twenty-five patients (81%) were women, and 30 patients (97%) had adenocarcinoma. The overall response rate was 74% (95% confidence interval, 58%-91%), and the disease control rate was 90%. The median progression-free survival was 12.3 months. The common adverse events were rash, diarrhea, and liver dysfunction. One treatment-related death because of interstitial lung disease occurred. This is the first study that verified safety and efficacy of first-line treatment with gefitinib in elderly patients having advanced NSCLC with EGFR mutation. Considering its strong antitumor activity and mild toxicity, first-line gefitinib may be preferable to standard chemotherapy for this population.
  Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2012; 7(9):1417-22. · 4.55 Impact Factor
• Article: Miliary brain metastases in 2 cases with advanced non-small cell lung cancer harboring EGFR mutation during gefitinib treatment.

  Sayaka Mochizuki, Naoki Nishimura, Akira Inoue, Koji Murakami, Toshihiro Nukiwa, Naohiko Chohnabayashi
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  ABSTRACT: Here we report 2 cases of non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) gene mutation that developed miliary brain metastases characterized by dementia and disorientation during gefitinib therapy. One patient's therapy was switched from gefitinib to chemotherapy followed by whole brain radiotherapy (WBRT), which resulted in disease progression with coma. Gefitinib reinitiation improved the patient's symptoms. The other patient continued gefitinib during WBRT and achieved complete remission of the miliary metastases and lived 18 months longer. These results suggest that gefitinib concomitant with WBRT is an optional strategy for the treatment of patients with EGFR-mutated NSCLC with miliary metastases to prevent disease flare.
  Respiratory investigation. 09/2012; 50(3):117-21.
• Article: Reduction of virulence factor pyocyanin production in multidrug-resistant Pseudomonas aeruginosa.

  Katsuhiro Fuse, Shigeru Fujimura, Toshiaki Kikuchi, Kazunori Gomi, Yasuhiro Iida, Toshihiro Nukiwa, Akira Watanabe
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  ABSTRACT: Nosocomial infections caused by metallo-β-lactamase (MBL)-producing multidrug-resistant (MDR) Pseudomonas aeruginosa have become a worldwide problem. Pyocyanin, a representative pigment produced by P. aeruginosa, is the major virulence factor of this organismThe aim of this study was to investigate the pyocyanin-producing ability of MBL-producing MDR P. aeruginosa. A total of 50 clinical isolates of P. aeruginosa, including 20 MDR strains, were collected at 18 general hospitals in Japan. The chromaticity and luminosity produced by pyocyanin in each isolate were measured. The quantity of pyocyanin and the expression of the phzM and phzS genes coding a pyocyanin synthesis enzyme were measured. MDR strains showed a bright yellow-green, while non-MDR strains tended to show a dark blue-green. The quantities of pyocyanin in MBL-producing strains and non-producing strains were 0.015 ± 0.002 and 0.41 ± 0.10 μg, respectively. The expression of the phzM and phzS genes in the MDR strains was 11 and 14 %, respectively, of the expression in the non-MDR strains. When the MBL gene was transduced into P. aeruginosa and it acquired multidrug resistance, it was shown that the pyocyanin-producing ability decreased. The pathogenicity of MBL-producing MDR P. aeruginosa may be lower than that of non-MDR strains. These MBL-producing MDR strains may be less pathogenic than non-MDR strains. This may explain why MDR-P. aeruginosa is unlikely to cause infection but, rather, causes subclinical colonization only.
  Journal of Infection and Chemotherapy 08/2012; · 1.80 Impact Factor
• Article: Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming.

  Yoichiro Mitsuishi, Keiko Taguchi, Yukie Kawatani, Tatsuhiro Shibata, Toshihiro Nukiwa, Hiroyuki Aburatani, Masayuki Yamamoto, Hozumi Motohashi
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  ABSTRACT: Cancer cells consume large quantities of nutrients and maintain high levels of anabolism. Recent studies revealed that various oncogenic pathways are involved in modulation of metabolism. Nrf2, a key regulator for the maintenance of redox homeostasis, has been shown to contribute to malignant phenotypes of cancers including aggressive proliferation. However, the mechanisms with which Nrf2 accelerates proliferation are not fully understood. Here, we show that Nrf2 redirects glucose and glutamine into anabolic pathways, especially under the sustained activation of PI3K-Akt signaling. The active PI3K-Akt pathway augments the nuclear accumulation of Nrf2 and enables Nrf2 to promote metabolic activities that support cell proliferation in addition to enhancing cytoprotection. The functional expansion of Nrf2 reinforces the metabolic reprogramming triggered by proliferative signals.
  Cancer cell 07/2012; 22(1):66-79. · 25.29 Impact Factor
• Source

  Available from: Toshiyuki Harada

  Article: Quality of life with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis of North East Japan Study Group 002 Trial.

  Satoshi Oizumi, Kunihiko Kobayashi, Akira Inoue, Makoto Maemondo, Shunichi Sugawara, Hirohisa Yoshizawa, Hiroshi Isobe, Masao Harada, Ichiro Kinoshita, Shoji Okinaga, Terufumi Kato, Toshiyuki Harada, Akihiko Gemma, Yasuo Saijo, Yuki Yokomizo, Satoshi Morita, Koichi Hagiwara, Toshihiro Nukiwa
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  ABSTRACT: For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, first-line gefitinib produced a longer progression-free survival interval than first-line carboplatin plus paclitaxel but did not show any survival advantage in the North East Japan 002 study. This report describes the quality of life (QoL) analysis of that study. Chemotherapy-naïve patients with sensitive EGFR-mutated, advanced NSCLC were randomized to receive gefitinib or chemotherapy (carboplatin and paclitaxel). Patient QoL was assessed weekly using the Care Notebook, and the primary endpoint of the QoL analysis was time to deterioration from baseline on each of the physical, mental, and life well-being QoL scales. Kaplan-Meier probability curves and log-rank tests were employed to clarify differences. QoL data from 148 patients (72 in the gefitinib arm and 76 in the carboplatin plus paclitaxel arm) were analyzed. Time to defined deterioration in physical and life well-being significantly favored gefitinib over chemotherapy (hazard ratio [HR] of time to deterioration, 0.34; 95% confidence interval [CI], 0.23-0.50; p < .0001 and HR, 0.43; 95% CI, 0.28-0.65; p < .0001, respectively). QoL was maintained much longer in patients treated with gefitinib than in patients treated with standard chemotherapy, indicating that gefitinib should be considered as the standard first-line therapy for advanced EGFR-mutated NSCLC in spite of no survival advantage.
  The Oncologist 05/2012; 17(6):863-70. · 3.91 Impact Factor
• Article: An ectopic ACTH-producing small cell lung carcinoma associated with enhanced corticosteroid biosynthesis in the peritumoral areas of adrenal metastasis.

  Hironori Satoh, Ryoko Saito, Shu Hisata, Jun Shiihara, Shinji Taniuchi, Yasuhiro Nakamura, Toshihiro Nukiwa, Masahito Ebina, Hironobu Sasano
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  ABSTRACT: A 60-year-old Japanese male presented with swelling of bilateral cervical lymph nodes was subsequently diagnosed as the late stage of primary small cell lung carcinoma (SCLC). He was then treated with cisplatin and irinotecan as first-line chemotherapy, but hypokalemia with muscle weakness of the bilateral legs became gradually noticeable following two months of effective chemotherapy. A computed tomography (CT) scan revealed enlargement of bilateral adrenal glands and abdominal and mediastinal lymph nodes, though primary lung tumor remained the same in size. An ectopic ACTH-producing syndrome (EAS) was subsequently revealed by the following endocrinological studies. Hypokalemia was clinically improved by the treatment with metyrapone and the second-line chemotherapy with amrubicin for SCLC was started, but the patient died 12 days after the second-line chemotherapy. Post-mortem examination revealed ACTH immunoreactivity in tumor cells of all the metastatic lesions. Non-neoplastic adrenal cortex demonstrated hyperplasia associated with lipid depletion and marked expression of steroidogenic enzymes, especially in cortical cells around tumor infiltration, suggestive of paracrine ACTH stimulation of cortisol production. This is the first report evaluating expression of steroidogenic enzymes in adrenal cortex especially adjacent to the adrenal metastasis in the patients with EAS due to SCLC. These findings suggest that ACTH producing adrenal metastasis can induce EAS more frequently and severely, and that the symptoms and examination of EAS should be monitored carefully in the patients with adrenal metastasis of SCLC.
  Lung cancer (Amsterdam, Netherlands) 01/2012; 76(3):486-90. · 3.14 Impact Factor
• Article: Bilateral peripheral infiltrates refractory to immunosuppressants were diagnosed as autoimmune pulmonary alveolar proteinosis and improved by inhalation of granulocyte/macrophage-colony stimulating factor.

  Hironori Satoh, Ryushi Tazawa, Tomohiro Sakakibara, Shinya Ohkouchi, Masahito Ebina, Makoto Miki, Koh Nakata, Toshihiro Nukiwa
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  ABSTRACT: A 55-year-old non-smoking woman was admitted to our hospital for re-evaluation of unimproved peripheral ground-glass opacities despite prednisolone and cyclosporine treatment. She was diagnosed with autoimmune pulmonary alveolar proteinosis (PAP) based on transbronchial lung biopsy and granulocyte/macrophage colony-stimulating factor (GM-CSF) antibody testing. GM-CSF inhalation therapy markedly improved the opacities. Bilateral, centrally located lung opacities are typical in PAP, however 10 PAP cases with peripheral infiltration were reported in Japan recently, of which GM-CSF antibody was positive in six. To avoid inappropriate immunosuppressant treatment, PAP should be considered in the differential diagnosis of such peripheral opacities. GM-CSF antibody might be useful for diagnosis.
  Internal Medicine 01/2012; 51(13):1737-42. · 0.94 Impact Factor
• Article: Altered expression of tight junction molecules in alveolar septa in lung injury and fibrosis.

  Hiromitsu Ohta, Shigeki Chiba, Masahito Ebina, Mikio Furuse, Toshihiro Nukiwa
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  ABSTRACT: The dysfunction of alveolar barriers is a critical factor in the development of lung injury and subsequent fibrosis, but the underlying molecular mechanisms remain poorly understood. To clarify the pathogenic roles of tight junctions in lung injury and fibrosis, we examined the altered expression of claudins, the major components of tight junctions, in the lungs of disease models with pulmonary fibrosis. Among the 24 known claudins, claudin-1, claudin-3, claudin-4, claudin-7, and claudin-10 were identified as components of airway tight junctions. Claudin-5 and claudin-18 were identified as components of alveolar tight junctions and were expressed in endothelial and alveolar epithelial cells, respectively. In experimental bleomycin-induced lung injury, the levels of mRNA encoding tight junction proteins were reduced, particularly those of claudin-18. The integrity of the epithelial tight junctions was disturbed in the fibrotic lesions 14 days after the intraperitoneal instillation of bleomycin. These results suggest that bleomycin mainly injured alveolar epithelial cells and impaired alveolar barrier function. In addition, we analyzed the influence of transforming growth factor-β (TGF-β), a critical mediator of pulmonary fibrosis that is upregulated after bleomycin-induced lung injury, on tight junctions in vitro. The addition of TGF-β decreased the expression of claudin-5 in human umbilical vein endothelial cells and disrupted the tight junctions of epithelial cells (A549). These results suggest that bleomycin-induced lung injury causes pathogenic alterations in tight junctions and that such alterations seem to be induced by TGF-β.
  AJP Lung Cellular and Molecular Physiology 01/2012; 302(2):L193-205. · 3.66 Impact Factor
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  Available from: PubMed Central

  Article: Targeting lysophosphatidic acid signaling retards culture-associated senescence of human marrow stromal cells.

  Masahiko Kanehira, Toshiaki Kikuchi, Shinya Ohkouchi, Taizou Shibahara, Naoki Tode, Arif Santoso, Hisayoshi Daito, Hiromitsu Ohta, Tsutomu Tamada, Toshihiro Nukiwa
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  ABSTRACT: Marrow stromal cells (MSCs) isolated from mesenchymal tissues can propagate in vitro to some extent and differentiate into various tissue lineages to be used for cell-based therapies. Cellular senescence, which occurs readily in continual MSC culture, leads to loss of these characteristic properties, representing one of the major limitations to achieving the potential of MSCs. In this study, we investigated the effect of lysophosphatidic acid (LPA), a ubiquitous metabolite in membrane phospholipid synthesis, on the senescence program of human MSCs. We show that MSCs preferentially express the LPA receptor subtype 1, and an abrogation of the receptor engagement with the antagonistic compound Ki16425 attenuates senescence induction in continually propagated human MSCs. This anti-aging effect of Ki16425 results in extended rounds of cellular proliferation, increased clonogenic potential, and retained plasticity for osteogenic and adipogenic differentiation. Expressions of p16(Ink4a), Rb, p53, and p21(Cip1), which have been associated with cellular senescence, were all reduced in human MSCs by the pharmacological inhibition of LPA signaling. Disruption of this signaling pathway was accompanied by morphological changes such as cell thinning and elongation as well as actin filament deformation through decreased phosphorylation of focal adhesion kinase. Prevention of LPA receptor engagement also promoted ubiquitination-mediated c-Myc elimination in MSCs, and consequently the entry into a quiescent state, G(0) phase, of the cell cycle. Collectively, these results highlight the potential of pharmacological intervention against LPA signaling for blunting senescence-associated loss of function characteristic of human MSCs.
  PLoS ONE 01/2012; 7(2):e32185. · 4.09 Impact Factor
• Article: Mesenchymal stromal cells protect cancer cells from ROS-induced apoptosis and enhance the Warburg effect by secreting STC1.

  Shinya Ohkouchi, Gregory J Block, Ahmed M Katsha, Masahiko Kanehira, Masahito Ebina, Toshiaki Kikuchi, Yasuo Saijo, Toshihiro Nukiwa, Darwin J Prockop
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  ABSTRACT: Previous studies have demonstrated that mesenchymal stromal cells (MSCs) enhance cell survival through upregulation and secretion of stanniocalcin-1 (STC1). This study shows that MSC-derived STC1 promotes survival of lung cancer cells by uncoupling oxidative phosphorylation, reducing intracellular reactive oxygen species (ROS), and shifting metabolism towards a more glycolytic metabolic profile. MSC-derived STC1 upregulated uncoupling protein 2 (UCP2) in injured A549 cells in an STC1-dependent manner. Knockdown of UCP2 reduced the ability of MSCs and recombinant STC1 (rSTC1) to reduce cell death in the A549 population. rSTC1-treated A549 cells displayed decreased levels of ROS, mitochondrial membrane potential (MMP), and increased lactate production, all of which were dependent on the upregulation of UCP2. Our data suggest that MSCs can promote cell survival by regulating mitochondrial respiration via STC1.
  Molecular Therapy 12/2011; 20(2):417-23. · 6.87 Impact Factor
• Article: Low-dose gefitinib treatment for patients with advanced non-small cell lung cancer harboring sensitive epidermal growth factor receptor mutations.

  Hironori Satoh, Akira Inoue, Kunihiko Kobayashi, Makoto Maemondo, Satoshi Oizumi, Hiroshi Isobe, Akihiko Gemma, Yasuo Saijo, Hirohisa Yoshizawa, Koichi Hagiwara, Toshihiro Nukiwa
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  ABSTRACT: Although standard schedule of gefitinib was the administration of 250 mg tablet every day, many patients need dose reduction because of toxicities. However, the efficacy of such low-dose gefitinib for patients with epidermal growth factor receptor-mutated non-small cell lung cancer has rarely been evaluated. A post hoc comparison of the efficacy (response rate and survival) in patients treated with gefitinib with or without any dose reduction in NEJ002 study was performed. Among 114 patients treated with first-line gefitinib in NEJ002, 61 (54%) continued gefitinib without any dose reduction until their diseases progressed, and 53 (46%) reduced their dose of gefitinib because of some toxicities. There was no significant difference of patient characteristics between the two groups. The progression-free survival of low-dose group tended to be better than that of standard-dose group (median progression-free survival, 11.8 versus 9.9 months; p = 0.144), and the overall survival of low-dose group was also better than that of standard-dose group (median survival time, 32.7 versus 25.3 months; p = 0.049). The results suggest that low-dose gefitinib may be clinically not inferior to standard-dose gefitinib for non-small cell lung cancer with sensitive epidermal growth factor receptor mutations. Prospective study of low-dose gefitinib is warranted especially for frail patients who need less toxic treatment.
  Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2011; 6(8):1413-7. · 4.55 Impact Factor
• Article: Toll-like receptor 4 potentiates Ca2+-dependent secretion of electrolytes from swine tracheal glands.

  Koji Murakami, Tsutomu Tamada, Masayuki Nara, Soshi Muramatsu, Toshiaki Kikuchi, Masahiko Kanehira, Yoshio Maruyama, Masahito Ebina, Toshihiro Nukiwa
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  ABSTRACT: Airway surface fluids are mainly secreted from submucosal glands, and play important roles in the defense of airways via the up-regulation of mucociliary transport, resulting in an exclusion of many microbes or foreign substances. Although there are many articles concerning the importance of Toll-like receptors (TLRs) in airway immune systems, whether TLRs directly cooperate with tracheal submucosal glands to increase secretion remains unknown. We investigated the effects of ligands of the three TLR subtypes (TLR2, TLR3, and TLR4) on the physiologic secretion of electrolytes by using a patch-clamp technique. Among these TLRs, only the TLR4 ligand, LPS, showed potentiating effects on acetylcholine (ACh)-induced ionic currents in a dose-dependent manner. These potentiating effects were completely abolished by pretreatment with a specific TLR4 antagonist or the anti-TLR4 antibody. LPS per se exerted no appreciable effect on baseline currents. Next, we demonstrated the abundant expression of TLR4 in submucosal gland acinar cells by using immunofluorescent staining and RT-PCR. Furthermore, we revealed that both nitric oxide synthase inhibitors and cyclic guanosine monophosphate (cGMP)-dependent protein kinase (cGK) inhibitors abolished the LPS-induced potentiating effects completely. Analyses of fluorescence intensities, using an intracellular nitric oxide (NO) indicator, demonstrated that LPS could further increase the ACh-induced synthesis of NO. These findings suggest that TLR4 takes part in airway mucosal defense systems as a unique exogenous potentiator of electrolyte-water secretion from submucosal gland acinar cells, and that NO/cGMP/cGK signaling is involved in this rapid TLR4 signaling pathway.
  American Journal of Respiratory Cell and Molecular Biology 06/2011; 45(5):1101-10. · 5.13 Impact Factor
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  Available from: PubMed Central

  Article: A case of cutaneous infection caused by mycobacterium szulgai with progression to acute respiratory distress syndrome.

  Hiromitsu Ohta, Eisaku Miyauchi, Masahito Ebina, Toshihiro Nukiwa
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  ABSTRACT: A 59-year-old man presented with a skin eruption and bilateral swelling of the legs. Soon after the initial presentation, he developed acute respiratory distress syndrome (ARDS) with miliary lung nodules. Culture of samples from the skin ulcers, sputum, and bronchoalveolar lavage fluid all revealed Mycobacterium szulgai infection. The patient was successfully treated with antituberculosis drugs. M. szulgai infection is very rarely reported worldwide, and disseminated infection usually occurs in immunocompromised patients. However, the present patient was a non-immunocompromised case, although he was a hepatitis B virus carrier. While the progression to ARDS from M. tuberculosis infection is well known, this is the first case of M. szulgai infection progressing to ARDS.
  Clinical medicine insights. Case reports. 01/2011; 4:29-33.
• Article: Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model.

  Ahmed M Katsha, Shinya Ohkouchi, Hong Xin, Masahiko Kanehira, Ruowen Sun, Toshihiro Nukiwa, Yasuo Saijo
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  ABSTRACT: Multipotent stromal cells (MSCs) ameliorate several types of lung injury. The differentiation of MSCs into specific cells at the injury site has been considered as the important process in the MSC effect. However, although MSCs reduce destruction in an elastase-induced lung emphysema model, MSC differentiation is relatively rare, suggesting that MSC differentiation into specific cells does not adequately explain the recuperation observed. Humoral factors secreted by MSCs may also play an important role in ameliorating emphysema. To confirm this hypothesis, emphysema was induced in the lungs of C57BL/6 mice by intratracheal elastase injection 14 days before intratracheal MSC or phosphate-buffered saline (PBS) administration. Thereafter, lungs were collected at several time points and evaluated. Our results showed that MSCs reduced the destruction in elastase-induced emphysema. Furthermore, double immunofluorescence staining revealed infrequent MSC engraftment and differentiation into epithelial cells. Real-time PCR showed increased levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF). Real-time PCR and western blotting showed enhanced production of secretory leukocyte protease inhibitor (SLPI) in the lung. In-vitro coculture studies confirmed the in vivo observations. Our findings suggest that paracrine factors derived from MSCs is the main mechanism for the protection of lung tissues from elastase injury.
  Molecular Therapy 01/2011; 19(1):196-203. · 6.87 Impact Factor
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  Available from: PubMed Central

  Article: Gradual increase of high mobility group protein b1 in the lungs after the onset of acute exacerbation of idiopathic pulmonary fibrosis.

  Masahito Ebina, Hiroyuki Taniguchi, Taku Miyasho, Shingo Yamada, Naoko Shibata, Hiromitsu Ohta, Shu Hisata, Shinya Ohkouchi, Tsutomu Tamada, Hidekazu Nishimura, Akitoshi Ishizaka, Ikuro Maruyama, Yoshinori Okada, Kondo Takashi, Toshihiro Nukiwa
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  ABSTRACT: The pathogenesis of acute exacerbation of idiopathic pulmonary fibrosis (IPF) remains to be elucidated. To evaluate the roles of inflammatory mediators in acute exacerbation, the concentrations of high mobility group protein B1 (HMGB1), a chief mediator of acute lung injury, and 18 inflammatory cytokines were measured in the bronchoalveolar lavage fluid, serially sampled from seven IPF patients after the onset of acute exacerbation. HMGB1 gradually increased in the alveolar fluid after the onset of acute exacerbation, in positive correlation with monocytes chemotactic protein-1 (MCP-1), a potent fibrogenic mediator. In the lung tissues of eight IPF patients autopsied after acute exacerbation, intense cytoplasmic staining for HMGB1 was observed in the alveolar epithelial cells in alveolar capillary augmented lesions, where the capillary endothelial cells remarkably reduced the expression of thrombomodulin, an intrinsic antagonist of HMGB1. These results suggest pathogenic roles for HMGB1 and MCP-1 in the late phase of acute exacerbation of IPF.
  Pulmonary medicine. 01/2011; 2011:916486.
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  Available from: PubMed Central

  Article: A Normal Range of KL-6/MUC1 Independent of Elevated SP-D Indicates a Better Prognosis in the Patients with Honeycombing on High-Resolution Computed Tomography.

  Shu Hisata, Yuichiro Kimura, Naoko Shibata, Shuichi Ono, Takao Kobayashi, Shigeki Chiba, Hiromitsu Ohta, Toshihiro Nukiwa, Masahito Ebina
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  ABSTRACT: Both SP-D and KL-6/MUC1 are established biomarkers of the interstitial pneumonias, including idiopathic pulmonary fibrosis (IPF), but the causes and clinical outcomes based on their independent effects are not known. Eleven asymptomatic patients, detected with honeycombing on high-resolution computed tomography (HRCT), were compared with 17 other IPF outpatients having slight respiratory symptoms and honeycombing as well. Although SP-D was increased in both groups, KL-6 was significantly higher in the symptomatic IPF group. When the patients (n = 11) having both biomarkers elevated were compared with the other patients (n = 6) with only SP-D elevated, the distribution of fibrotic lesions with honeycombing on HRCT was larger and the survival time was shorter in the patients having both biomarkers elevated. Immunohistochemical analysis also differentiated these biomarkers in the lung. These results suggest both a cause and the prognostic value of dissociation of these biomarkers.
  Pulmonary medicine. 01/2011; 2011:806014.