Masaki Watanabe

Kagoshima University, Kagosima, Kagoshima, Japan

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Publications (23)99.34 Total impact

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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease associated with significant morbidity and mortality. Although several oral phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of COPD, their use has been restricted because of side effects including nausea and emesis. We hypothesized that delivery of a dry powdered PDE4 inhibitor by inhalation would minimize systemic absorption and enable local PDE4 inhibition to suppress inflammation within the lung. Neutrophilic pulmonary inflammation was induced in mice by intratracheal administration of lipopolysaccharide. Mice were treated intratracheally with a new dry powder PDE4 inhibitor, E6005 (methyl 4-[({3-[6,7-dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl}amino) carbonyl] benzoate). The pharmacokinetics, cell profiles and levels of cytokines, chemokines, and lipid mediators in bronchoalveolar lavage fluid (BALF), and lung histology were assessed. Intratracheal administration of E6005 to mice resulted in high concentrations of the compound in the lungs. Histological analysis of E6005-treated mice demonstrated reduced inflammation of lung tissue that correlated with a decrease in BALF levels of neutrophils, proinflammatory cytokines, chemokines, and cysteinyl leukotrienes. Thus, intratracheal administration of E6005 effectively suppresses neutrophilic pulmonary inflammation, suggesting that the new inhaled dry powder PDE4 inhibitor represents an alternative to the conventional oral formulation for treating COPD.
    No preview · Article · Oct 2015 · European journal of pharmacology
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    ABSTRACT: Background Interstitial lung diseases (ILDs) are common in patients with connective tissue diseases (CTDs). Although the diagnosis of an underlying CTD in ILD (CTD-ILD) affects both prognosis and treatment, it is sometimes difficult to distinguish CTD-ILD from chronic fibrosing interstitial pneumonia (CFIP). B cell–activating factor belonging to the tumour necrosis factor family (BAFF) plays a crucial role in B cell development, survival, and antibody production. Methods We examined serum levels of BAFF, surfactant protein D (SP-D), and Krebs von den Lungen-6 (KL-6) in 33 patients with CTD-ILD, 16 patients with undifferentiated CTD-ILD, 19 patients with CFIP, and 26 healthy volunteers. And we analysed the relationship between serum BAFF levels and pulmonary function, as well as the expression of BAFF in the lung tissue of patients with CTD-ILD. Results Serum levels of BAFF were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. However, there were no significant differences in serum levels of SP-D and KL-6. Furthermore, serum BAFF levels in CTD-ILD patients were inversely correlated with pulmonary function. BAFF was strongly expressed in the lungs of CTD-ILD patients, but weakly in normal lungs. Discussion This is the first study to demonstrate that serum BAFF levels were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. Furthermore, serum BAFF levels were correlated with pulmonary function. We consider that serum BAFF levels in patients with CTD-ILD reflect the presence of ILDs disease activity and severity. Conclusion These finding suggest that BAFF may be a useful marker for distinguishing CTD-ILD from CFIP.
    Preview · Article · Sep 2015 · BMC Pulmonary Medicine
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    Masaki Watanabe · Kentaro Machida · Hiromasa Inoue
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    ABSTRACT: Leukotriene B4 (LTB4), a potent lipid mediator of inflammation derived from arachidonic acid through the action of 5-lipoxygenase, has been implicated in the pathophysiology of several inflammatory diseases, including asthma and chronic obstructive pulmonary disease. A high-affinity LTB4 receptor BLT1 has been shown to exert proinflammatory roles. A cyclooxygenase metabolite, 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT), is an endogenous ligand for BLT2, a low-affinity LTB4 receptor. The recent study indicated that BLT2 has a protective role in allergic airway inflammation, suggesting different functions between BLT1 and BLT2 in the pathogenesis of asthma. Selective BLT1 antagonists may have a potential therapeutic application in patients with asthma, and BLT2 may represent a novel therapeutic target for lung diseases.
    Preview · Article · Apr 2014 · Expert Review of Respiratory Medicine

  • No preview · Article · Dec 2008 · The Journal of Immunology
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    Preview · Article · Dec 2008 · The Journal of Immunology
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    Preview · Article · Dec 2008 · The Journal of Immunology
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    Preview · Article · Nov 2008 · Blood
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    Preview · Article · Sep 2008 · Arthritis & Rheumatology
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    ABSTRACT: The chemokine receptor CXCR4, which binds the chemokine stromal cell-derived factor 1, has been reported to be involved in the chemotaxis of inflammatory cells. In addition, AMD3100, an antagonist of CXCR4, has been reported to be an attractive drug candidate for therapeutic intervention in several disorders in which CXCR4 is critically involved. However, little is known about the therapeutic value of AMD3100 in the treatment of pulmonary fibrosis. In this study, we examined the effects of AMD3100 on a murine bleomycin-induced pulmonary fibrosis model. Concurrent administration of AMD3100 and bleomycin apparently attenuated bleomycin-induced pulmonary inflammation. In this process, an inhibition of neutrophil recruitment at early stage followed by the decrease of other inflammatory cell recruitment in the lung were observed. In addition, it also inhibited the expression of cytokines, including MCP-1, MIP-2, MIP-1alpha, and TGF-beta. In contrast, when AMD3100 was administered following bleomycin treatment, the bleomycin-induced lung inflammation progressed and resulted in severe pulmonary fibrosis. In this process, an increase of inflammatory cell recruitment, an up-regulation of lung MCP-1 and TGF-beta, and a remarkable activation of p44/42 MAPK in neutrophils were observed. U0126, an inhibitor of p44/42 MAPK, significantly abolished these effects. Thus, AMD3100 has dual effect on bleomycin-induced pulmonary fibrosis. Difference of inflammatory cell recruitment and activation might be associated with the dual effect of AMD3100 on bleomycin-induced pulmonary fibrosis.
    Preview · Article · Jun 2007 · The Journal of Immunology
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    ABSTRACT: Prolonged survival of eosinophils plays an important role in the pathogenesis of Churg-Strauss syndrome (CSS); however, its detailed molecular mechanism is still unclear. TRAIL and its receptors are expressed on a variety of cells, including eosinophils. In this study, we examined the expression of TRAIL receptors on eosinophils from patients with CSS. TRAIL receptor expression was assessed on eosinophils from healthy volunteers, patients with CSS, patients with asthma, and patients with hypereosinophilia due to parasitic infection. TRAIL-induced apoptosis of eosinophils was compared between the patients with CSS and patients with asthma. RNA interference was used to assess the effects of suppression of TRAIL receptor 3. Expression of TRAIL receptor 3, a decoy receptor that acts as an antiapoptotic receptor, on eosinophils from patients with CSS was significantly higher than that in the other subjects. Moreover, in CSS, serum TRAIL receptor 3 levels showed a significant positive correlation with peripheral eosinophil counts, tissue-infiltrating eosinophils stained positive for this receptor, and peripheral T cells expressed TRAIL on their surface. Compared with asthma patients, eosinophils from CSS patients showed a significantly lower percentage of recombinant TRAIL, less autologous T cell-induced apoptosis, and decreased level of active caspase 3. Suppression of TRAIL receptor 3 through RNA interference significantly increased the recombinant TRAIL-induced apoptosis of eosinophils from CSS patients. Increased expression of TRAIL receptor 3 on eosinophils from patients with CSS was observed. These alterations in TRAIL receptor 3 expression might be involved in the molecular pathogenesis of CSS eosinophilia.
    Preview · Article · Feb 2007 · Arthritis & Rheumatology
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    ABSTRACT: Microscopic polyangiitis (MPA) is a systemic necrotizing vasculitis that affects small vessels, resulting in a wide spectrum of organ involvement including the lungs. However, there are little serological markers that predict its prognosis or severity of pulmonary involvement. Vascular endothelial growth factor (VEGF) is an angiogenic mediator, which has been reported to be elevated in systemic vasculitis. In this study, we measured serum VEGF levels in 22 MPA patients with pulmonary involvement. We also investigated VEGF expression in pulmonary cells using flow cytometry analysis. We found that serum VEGF levels in MPA patients were significantly higher than those in respiratory or urinary tract infection. The serum VEGF levels decreased in parallel with the improvement of MPA symptoms. The serum VEGF levels in MPA patients who died within 5 years were significantly higher than those who survived more than 5 years. The sensitivity of VEGF levels to distinguish MPA patient with poor prognosis from those with good prognosis was 90.9%, and specificity was 81.8% (cutoff value = 802.5 pg/ml). The serum VEGF levels showed significant positive correlation with the composite physiological index, which indicates the severity of pulmonary lesion. In flow cytometry analysis, CD11b positive bronchoalveolar lavage fluid cells expressed VEGF. Immunohistochemically, alveolar macrophages, tissue infiltrating inflammatory cells and alveolar epithelial cells stained positive for VEGF. Measurement of serum VEGF levels in MPA might become one of the markers for prognosis and the severity of pulmonary involvement in MPA. VEGF might contribute to the development of pulmonary lesion of MPA.
    Preview · Article · Nov 2006 · Respiratory Medicine
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    ABSTRACT: Case 1 is a 78-year-old woman in whom lung adenocarcinoma with multiple brain metastasis (cT2N3M1, stage IV) was diagnosed. She was treated with Gefitinib alone. Her lung tumor and metastatic brain lesions decreased 6 months after the start of therapy. She has no recurrence and is still alive with a good performance status after 25 months. Case 2 is an 80-year-old woman in whom lung adenocarcinoma with multiple brain (cT2N3M1, stage IV) was diagnosed. She was also treated with Gefitinib alone and her lung tumor and metastatic brain becomes improved 6 months after the start of therapy. She maintained a good performance status for more than 2 years (29 months). However, 29 months after beginning treatment, she had recurrence in bone and died 2 months later, 31 months after the start of therapy. The prognosis of non-small cell lung cancer with multiple brain metastasis is very poor and the efficacy of chemotherapy for the treatment of multiple brain metastases is limited, and longterm survival remains disappointing. We report two lung adenocarcinoma patients with multiple brain metastasis who survived more than 2 years by treatment with Gefitinib alone.
    No preview · Article · Oct 2006
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    ABSTRACT: A 48-year-old woman was admitted with dyspnea on effort. She suffered from adult T-cell leukemia and received peripheral blood stem cell transplantation (PBSCT). Eight months after the PBSCT, she developed dyspnea on effort and was treated with bronchodilator, inhaled corticosteroid, anti-leukotriene drug, theophylline and oxytropium bromide. However her symptoms progressed and she was admitted. We diagnosed bronchiolitis obliterans syndrome (BOS) because of obstructive pulmonary dysfunction, diffuse patchy high density of the lung field on chest computed tomography and decreased ventilation with peripheral patchy accumulation on ventilation scintigraphy. She was treated with corticosteroid and cyclosporine A and her symptoms and her pulmonary function were improved. However, in parallel with corticosteroid tapering, her symptoms and pulmonary functions worsened. Treatment with Tiotropium bromide was started and her pulmonary function improved significantly. Her pulmonary function did not worsen and tapering steroid dose was successfully achieved. PBSCT was reported to up-regulate the muscarinic receptor activity in lung. Tiotropium bromide might become one additional option for the treatment of BOS.
    No preview · Article · Jun 2006
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast proliferation and accumulation of extracellular matrix, including collagen, is a chronic progressive disorder that results in lung remodeling and fibrosis. However, the cellular mechanisms that may make fibroblasts resistant to apoptosis have not been completely elucidated. Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase whose ligand is collagen, is expressed in vivo and contributes in vitro to leukocyte differentiation and nuclear factor (NF)-kappaB activation, which may play an important role in fibroblast survival. In this study, we examined in vivo and in vitro DDR1 expression and its role in cell survival using fibroblasts obtained from IPF and non-IPF patients. Immunohistochemically, fibroblasts present in fibroblastic foci expressed endogenous DDR1. The DDR1 expression level was significantly higher in fibroblasts from IPF patients, and the predominant isoform was DDR1b. In IPF patients, DDR1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-kappaB nuclear translocation. Suppression of DDR1 expression in fibroblasts by siRNA abolished these effects, and an NF-kappaB inhibitor abrogated the anti-apoptotic effect of DDR1 activation. We propose that DDR1 contributes to fibroblast survival in the tissue microenvironment of IPF and that DDR1 up-regulation may occur in other fibroproliferative lung diseases as well.
    No preview · Article · Apr 2006 · American Journal Of Pathology
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    ABSTRACT: Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase whose ligand is collagen. Recently, we have reported the association of DDR1 in the cytokine production of human leukocytes in in vitro and in vivo expression in idiopathic pulmonary fibrosis. However, its role in in vivo inflammation has not been fully elucidated. Small interference RNA (siRNA) can induce specific suppression of in vitro and in vivo gene expression. In this study, using a bleomycin-induced pulmonary fibrosis mouse model, we administered siRNA against DDR1 transnasally and evaluated histological changes, cytokine expression, and signaling molecule activation in the lungs. Histologically, siRNA against DDR1 successfully reduced in vivo DDR1 expression and attenuated bleomycin-induced infiltration of inflammatory cells. Furthermore, it significantly reduced inflammatory cell counts and concentrations of cytokines such as MCP-1, MIP-1alpha, and MIP-2 in bronchoalveolar lavage fluid. Subsequently, bleomycin-induced up-regulation of TGF-beta in bronchoalveolar lavage fluid was significantly inhibited, and collagen deposition in the lungs was reduced. Furthermore, siRNA against DDR1 significantly inhibited bleomycin-induced P38 MAPK activation in the lungs. Considered together, we propose that DDR1 contributes to the development of bleomycin-induced pulmonary inflammation and fibrosis.
    Preview · Article · Mar 2006 · The Journal of Immunology
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    ABSTRACT: Churg-Strauss syndrome (CSS) is a rare form of systemic vasculitis occurring in patients with asthma and hypereosinophilia. For optimal treatment, prompt distinction of CSS from asthma is necessary; however, there are few serologic screening markers for this purpose. Vascular endothelial growth factor (VEGF), a vascular permeability factor, has been associated with other systemic vasculitis such as Wegener granulomatosis and giant-cell arteritis. The aim of this study was to clarify the clinical value of the measurement of serum VEGF for the distinction of CSS from asthma. We investigated serum VEGF levels in 18 CSS patients, 19 asthma patients, and 12 acute bronchitis patients. We also performed immunohistochemical analysis for VEGF. The serum VEGF levels of CSS patients were significantly higher than those of asthma patients and acute bronchitis patients. The sensitivity and specificity to distinguish CSS from asthma were 93.3% and 81.8%, respectively (cutoff, 600 pg/mL). Infiltrating eosinophils stained intensely positive for VEGF, and serum VEGF levels showed a significant correlation with peripheral eosinophil counts. Serum VEGF levels decreased significantly after therapy (p < 0.001). The infiltrating eosinophils in the CSS lesion stained positive for VEGF in the immunohistochemical analysis. VEGF is one of the useful screening markers for the distinction of CSS from asthma. We suggest that VEGF might be associated with the pathogenesis of CSS.
    No preview · Article · Mar 2006 · Chest
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    ABSTRACT: The prognosis of sarcoidosis with pulmonary infiltrates differs in each case, and several cytokines are reported to contribute to its deterioration. However, the detailed mechanism has not been fully elucidated. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen and associated with cytokine production from inflammatory cells. We previously reported the functional expression of DDR1 on CD14-positive bronchoalveolar lavage fluid (BALF) cells in vivo. In this study, we hypothesized that DDR1 might be associated with the deterioration of pulmonary sarcoidosis (PS), and investigated 33 patients with sarcoidosis with pulmonary infiltrates, prospectively. We found that patients with deteriorated PS showed significantly higher DDR1 expression in CD14-positive BALF cells predominant with DDR1b isoforms. Activation of DDR1 induced monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) production in a p38 mitogen-activated protein kinase-dependent manner from CD14-positive BALF cells of patients with deteriorated sarcoidosis. DDR1 activation also induced NF-kappaB nuclear translocation in CD14-positive BALF cells of patients with deteriorated PS. The inhibitor of NF-kappaB inhibited the production of MCP-1 and MMP-9. We propose that DDR1 is associated with the deterioration of pulmonary sarcoidosis.
    Preview · Article · Jan 2006 · American Journal of Respiratory Cell and Molecular Biology
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    ABSTRACT: COPD, the fifth-leading cause of death worldwide, is characterized by chronic inflammation. However, no available agent can effectively cure this inflammation. A dietary supplement containing omega-3 polyunsaturated fatty acids (PUFAs) has anti-inflammatory effects. In this study, we hypothesized that nutritional support with omega-3 PUFA-rich diets may be useful for treating COPD, and we compared the clinical features and inflammatory mediator levels between the COPD patients who received an omega-3 PUFA-rich supplement and those who received a nonrich supplement. Sixty-four COPD patients received 400 kilocalories per day of an omega-3 PUFA-rich supplement (n-3 group) or an omega-3 PUFA-nonrich supplement (n-6 group) for 2 years. We prospectively investigated the clinical features of these patients and measured the levels of inflammatory mediators. In 6-min walk testing, the dyspnea Borg scale and decrease of arterial oxygen saturation measured by pulse oximetry significantly improved in the n-3 group. Leukotriene B4 levels in serum and sputum and tumor necrosis factor-alpha and interleukin-8 levels in sputum decreased significantly in the n-3 group, while there was no significant change in the n-6 group. Two patients in the n-3 group and three patients in the n-6 group had mild diarrhea, and three patients in the n-3 group and three patients in the n-6 group had nausea; however, their symptoms were controllable and they improved with treatment. With multiple regression analysis, it was proved that the omega-3 PUFA-rich diet significantly contributed to the change in cytokine levels in this study. We suggest nutritional support with an omega-3 PUFA-rich diet as a safe and practical method for treating COPD.
    No preview · Article · Jan 2006 · Chest

  • No preview · Article · Nov 2005 · Internal Medicine
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    ABSTRACT: We report a case of Hermansky-Pudlak syndrome (HPS) with a novel mutation in the HPS1 gene. This case showed oculocutaneous albinism and lysosomal ceroid accumulation, however platelet dysfunction was not observed. Histopathological findings of the biopsied lung tissue were compatible with HPS. Sequencing analysis showed the insertion of C in the codon 178 (739 bp) of the HPS1 gene forming a stop codon at codon 181. To the best of our knowledge, this is a novel HPS1 gene mutation.
    No preview · Article · Aug 2005 · Internal Medicine

Publication Stats

252 Citations
99.34 Total Impact Points

Institutions

  • 2005-2015
    • Kagoshima University
      • • Graduate School of Medical and Dental Sciences
      • • Department of Internal Medicine
      Kagosima, Kagoshima, Japan