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Tomomi Ichikawa,
Ryuji Hayashi, Kensuke Suzuki,
Shingo Imanishi,
Kenta Kambara,
Seisuke Okazawa,
Minehiko Inomata,
Toru Yamada,
Yu Yamazaki,
Yukiko Koshimizu,
Toshiro Miwa,
Shoko Matsui,
Isao Usui,
Masaharu Urakaze,
Yuji Matsuya,
Masakiyo Sasahara,
Kazuyuki Tobe
[show abstract]
[hide abstract]
ABSTRACT: SUMMARY AT A GLANCE: We investigated the effect of Sirt1 activator SRT1720 on an inflammatory model of asthma. SRT1720 suppressed inflammatory cell infiltration and cytokine production in an OVA-challenged mouse model. SRT1720 and resveratrol also directly suppressed OVA-induced splenocyte proliferation and TNFα and IL-6 production. SRT1720 has potential as a therapeutic drug for asthma. ABSTRACT: Background and Objective: In asthma, reduced histone deacetylase (HDAC) activity and enhanced histone acetyltransferase (HAT) activity in the lungs have been reported. However, the precise function of Sirtuin 1 (Sirt1), a class III HDAC, and the effect of the Sirt1 activator SRT1720 on allergic inflammation have not been fully elucidated. Methods: We investigated the effect of SRT1720, a synthetic activator of Sirt1, in a ovalbumin (OVA)-induced asthma mouse model. We also examined the effect of SRT1720 and resveratrol on OVA stimulation in splenocytes from OVA-sensitized and challenged mice. Results: In OVA-sensitized and challenged mice (OVA-mice) compared with saline-sensitized and challenged mice (control-mice), Sirt1 mRNA expression in the lungs was decreased (P =0.02) while cellular infiltration, airway eosinophilia and bronchoalveolar lavage (BAL) fluid levels of Interleukin (IL)-4, IL-5 and IL-13 were increased (P< 0.01). In OVA-mice, SRT1720 treatment decreased total and eosinophil cell counts and IL-5 and IL-13 levels in the BAL fluid compared with the vehicle treatment (P< 0.05). In OVA-mice, SRT1720 treatment also decreased inflammatory cell lung infiltrates histologically (P =0.002). Both SRT1720 and resveratrol suppressed OVA-induced cell proliferation and IL-6 (P< 0.05) and tumor necrosis factor alpha (TNFα) (P< 0.05) production in splenocytes (P< 0.01). Conclusions: The Sirt1 activator SRT1720 suppressed inflammatory cell infiltration and cytokine production in an OVA-induced mouse model of asthma. SRT1720 and resveratrol suppressed OVA-induced splenocyte proliferation and TNFα and IL-6 production. Sirt1 activators might have beneficial effects in asthmatics by suppressing inflammation. © 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.
Respirology 10/2012; · 2.42 Impact Factor
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Minehiko Inomata,
Ryuji Hayashi,
Kenta Kambara,
Seisuke Okazawa,
Shingo Imanishi,
Tomomi Ichikawa, Kensuke Suzuki,
Toru Yamada,
Toshiro Miwa,
Tatsuhiko Kashii,
Shoko Matsui,
Kazuyuki Tobe,
Masakiyo Sasahara
[show abstract]
[hide abstract]
ABSTRACT: Miliary brain metastasis is an extremely rare form of brain metastasis which can present with atypical imaging findings. We report the case of a patient with miliary brain metastasis of lung cancer showing calcification in metastatic lesions.
A 68-year-old Japanese woman was diagnosed with lung adenocarcinoma. Brain computed tomography revealed multiple small calcified lesions in both cerebral hemispheres. Mutation of the epidermal growth factor receptor gene (exon 21, L858R) in lung cancer cells was detected, and treatment with gefitinib was initiated. A partial response was observed; however, the patient was readmitted to our hospital because of regrowth of the primary lesion and complaints of nausea, headache, and difficulty walking. Brain magnetic resonance imaging revealed scattered tiny nodules enhanced by gadolinium. A diagnosis of leptomeningeal carcinomatosis was made on the basis of cerebrospinal fluid cytology. The patient's general status worsened, and she died 356 days after the day of first medical examination. Upon autopsy, the brain was found to be edematous and swollen. Lung carcinoma cells were diffusely disseminated on the meningeal surface. Metastatic foci of small nodular form, accompanied by calcifications, were also found in the brain parenchyma. We diagnosed miliary metastasis of lung carcinoma.
To the best of our knowledge, this is the third report of calcified miliary brain metastasis confirmed by autopsy. We describe calcified lesions that increased in size during the clinical course of nine months. Brain computed tomography findings that reveal multiple small calcified lesions in patients with malignancy should raise suspicion of miliary brain metastasis.
Journal of Medical Case Reports 09/2012; 6(1):279.
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Kensuke Suzuki,
Ryuji Hayashi,
Tomomi Ichikawa,
Shingo Imanishi,
Toru Yamada,
Minehiko Inomata,
Toshiro Miwa,
Shoko Matsui,
Isao Usui,
Masaharu Urakaze,
Yuji Matsuya,
Hirofumi Ogawa,
Hiroaki Sakurai,
Ikuo Saiki,
Kazuyuki Tobe
[show abstract]
[hide abstract]
ABSTRACT: Silent information regulator 2 (SIR2) is a highly conserved protein, the mammalian orthologue of which, SIRT1, exhibits histone deacetylase activity. SIRT1 is involved not in only longevity due to caloric restriction but in a variety of diseases such as diabetes, cardiovascular dysfunction and neurodegeneration. However, accumulating evidence shows that SIRT1 is overexpressed in various types of malignant cells, and its inhibitors suppress the growth of tumor cells. The relationship between SIRT1 and metastasis remains to be clarified. Here, we examined the effect of SRT1720, a SIRT1 activator, on lung metastasis of breast cancer cells. 4T1 breast cancer cells were subcutaneously implanted into syngeneic BALB/c mice and SRT1720 was administered alone or with an antitumor agent, cisplatin. As expected, cisplatin decreased the lung metastasis score, whereas SRT1720 increased metastasis irrespective of cisplatin. In the primary tumors, cisplatin suppressed the mRNA level of angiopoietin-like protein 4 (angptl4), a lung metastasis-promoting gene product of breast cancer, but SRT1720 reduced the effectiveness of cisplatin. The results obtained with animal experiments were in accordance with those in human cancer cells; SRT1720 significantly increased the amount of VEGF secreted from MDA-MB-231 cells. Moreover, a transendothelial cell migration assay showed that SRT1720 promotes the migration of MDA-MB-231 cells across an endothelial cell layer despite the presence of cisplatin. These findings imply that SRT1720 promotes the pulmonary metastasis of breast cancer cells and SIRT1 may be an important target for suppressing metastasis to the lung.
Oncology Reports 06/2012; 27(6):1726-32. · 1.84 Impact Factor
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Shoko Matsui,
Hirofumi Taki,
Koichiro Shinoda, Kensuke Suzuki,
Ryuji Hayashi,
Kazuyuki Tobe,
Yoshiharu Tokimitsu,
Masayuki Ishida,
Hiroaki Fushiki,
Hikaru Seto,
Junya Fukuoka,
Shin Ishizawa
[show abstract]
[hide abstract]
ABSTRACT: ‘Immunoglobulin G4 (IgG4)-related disease’ is a new clinical concept of multi-organ diseases, with Mikulicz’s disease (MD)
being a clinical phenotype of IgG4-related disease. To clarify the clinical characteristics of respiratory involvement associated
with IgG4-related MD, we retrospectively assessed 25 patients with MD, 11 (44%) of whom had allergic symptoms, and 7 (28%)
of whom complained of respiratory problems. Thirteen patients (52%) presented with pulmonary and/or mediastinal lesions (P-MD)
on chest computed tomography (CT), and 11 (44%) had lesions limited to the lacrimal and/or salivary glands (L-MD). Mean serum
total protein, IgG, and IgG4 concentrations were significantly higher and CH50 was significantly lower in the P-MD than in
the L-MD group. Immune complex was present only in the P-MD group. Chest CT images showed bronchial wall thickening, consolidation,
nodule(s), interlobular thickening, ground glass opacity, pleural thickening/effusion, and mediastinal lymphadenopathy. Five
of seven patients who underwent histological examination of the lungs had abundant IgG4-positive plasma cell infiltrates (IgG4/IgG-positive
plasma cells >40%), but the other two did not. These findings suggest that respiratory lesions are not rare in patients with
IgG4-related MD, and that they present with various manifestations. IgG4-related MD should be differentiated from similar
diseases, such as sarcoidosis, bronchial asthma, Sjögren’s syndrome, and malignant lymphoma.
KeywordsIgG4-related disease–Mikulicz’s disease–Respiratory involvement–Autoimmune pancreatitis
Modern Rheumatology 04/2012; 22(1):31-39. · 1.58 Impact Factor
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Shoko Matsui,
Hirofumi Taki,
Koichiro Shinoda, Kensuke Suzuki,
Ryuji Hayashi,
Kazuyuki Tobe,
Yoshiharu Tokimitsu,
Masayuki Ishida,
Hiroaki Fushiki,
Hikaru Seto,
Junya Fukuoka,
Shin Ishizawa
[show abstract]
[hide abstract]
ABSTRACT: 'Immunoglobulin G4 (IgG4)-related disease' is a new clinical concept of multi-organ diseases, with Mikulicz's disease (MD) being a clinical phenotype of IgG4-related disease. To clarify the clinical characteristics of respiratory involvement associated with IgG4-related MD, we retrospectively assessed 25 patients with MD, 11 (44%) of whom had allergic symptoms, and 7 (28%) of whom complained of respiratory problems. Thirteen patients (52%) presented with pulmonary and/or mediastinal lesions (P-MD) on chest computed tomography (CT), and 11 (44%) had lesions limited to the lacrimal and/or salivary glands (L-MD). Mean serum total protein, IgG, and IgG4 concentrations were significantly higher and CH50 was significantly lower in the P-MD than in the L-MD group. Immune complex was present only in the P-MD group. Chest CT images showed bronchial wall thickening, consolidation, nodule(s), interlobular thickening, ground glass opacity, pleural thickening/effusion, and mediastinal lymphadenopathy. Five of seven patients who underwent histological examination of the lungs had abundant IgG4-positive plasma cell infiltrates (IgG4/IgG-positive plasma cells >40%), but the other two did not. These findings suggest that respiratory lesions are not rare in patients with IgG4-related MD, and that they present with various manifestations. IgG4-related MD should be differentiated from similar diseases, such as sarcoidosis, bronchial asthma, Sjögren's syndrome, and malignant lymphoma.
Modern Rheumatology 08/2011; 22(1):31-9. · 1.58 Impact Factor
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Minehiko Inomata,
Yukio Kawagishi,
Kotaro Tokui,
Yasuaki Masaki,
Chihiro Taka,
Kenta Kambara,
Seisuke Okazawa,
Shingo Imanishi,
Tomomi Ichikawa, Kensuke Suzuki,
Toru Yamada,
Minoru Iwata,
Isao Usui,
Shigeki Sumi,
Hideki Origasa,
Shoko Matsui,
Ryuji Hayashi,
Kazuyuki Tobe
[show abstract]
[hide abstract]
ABSTRACT: We conducted a cross-sectional study to investigate which factors have a significant impact on wheezing and QOL in the elderly of a Japanese local community.
In 2008, 527 participants (250 participants aged 45 to 64 years and 277 participants aged 65 to 88 years) responded to the questionnaire regarding wheezing and disease history. QOL was evaluated by the Short Form-8. The participants underwent airway reversibility testing. The plasma levels of IgE were measured. The plasma levels of N-terminal-pro-B-type natriuretic peptide were measured in twenty-one participants with a history of ischemic heart disease and in thirty-five age-matched participants without that history.
Wheezing was reported by 50 (9.5%) participants and was associated with a lower score of QOL. In multivariate analysis, wheezing was associated with sex (OR 3.12, CI 1.10-9.67) and a history of bronchial asthma (OR 22.3, CI 6.50-84.0) among participants aged 45 to 64 years. Among participants aged 65 and over, wheezing was associated with a history of bronchial asthma (OR 4.86, CI 1.39-15.1) and ischemic heart disease (OR 5.12, CI 1.61-15.0). Participants with both a history of ischemic heart disease and wheezing showed higher levels of N-terminal-pro-B-type natriuretic peptide. Airway reversibility was only associated with a history of ischemic heart disease (OR 4.65, CI 1.26-17.6).
It is suggested that bronchial asthma and heart disease are both significant causes of wheezing and affect the QOL in the elderly of a Japanese local community.
Internal Medicine 01/2011; 50(24):2975-81. · 0.94 Impact Factor
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Koutarou Miyabayashi,
Muneharu Maruyama,
Toru Yamada,
Chie Shinoda,
Hiroyuki Hounoki,
Yukiko Kanatani,
Kouichirou Shinoda,
Yukio Kawagishi,
Toshiro Miwa, Kensuke Suzuki,
Nobuki Arai,
Ryuji Hayashi,
Shoko Matsui,
Eiji Sugiyama,
Masashi Kobayashi
[show abstract]
[hide abstract]
ABSTRACT: It has been reported that beta2-agonists may potentially exert some anti-inflammatory action in addition to bronchodilation that may contribute to their beneficial effects on asthma control. Bronchial epithelial cells are well known to respond to a range of stimuli by producing various biologically active mediators that can influence airway inflammation. RANTES (regulated on activation, normal T cells expressed and secreted) plays an important role in the pathophysiology of airway inflammation of asthmatics through its chemotactic activity for eosinophils. In this study, the authors investigated whether cytokine-induced RANTES release from BEAS-2B human bronchial epithelial cells could be modulated by beta-agonist isoproterenol (ISO). The possible involvement of c-jun N-terminal kinase (JNK) pathway was also studied. Combination of tumor necrosis factor-alpha and interleukin-1beta (cytokine mix) increased RANTES release from BEAS-2B cells and stimulated JNK activity. Similar to JNK inhibitor SP600125, ISO inhibited not only the production of RANTES but also the activation of JNK pathway in cytokine mix-stimulated BEAS-2B cells. The effect of ISO was mediated by the beta2-adrenoceptor, since it was blocked by ICI 118,551, a selective beta2-receptor antagonist, but not by atenolol, a selective beta1-receptor antagonist. Adenylyl cyclase activator forskolin reproduced the effects of ISO. Isoproterenol was found to inhibit the release of RANTES from the human bronchial epithelial cells, at least in part, through the inhibition of JNK signaling pathway.
Biochemical and Biophysical Research Communications 12/2006; 350(3):753-61. · 2.48 Impact Factor
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[show abstract]
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ABSTRACT: A 24-year-old woman was referred to another hospital because of a barking cough, but her chest radiograph showed no abnormality. Although she had been diagnosed as having other diseases and had been given medical treatment, the barking cough continued. Abnormalities of the chest radiograph appeared 11 months later, and endobronchial tuberculosis was diagnosed from the clinical history, chest CT and a sputum smear positive for acid-fast bacilli. We treated her with INH, RFP, EB for 6 months, and PZA for 2 months. However, truncus intermedius became obstructed nine months after treatment ended, and we re-opened it with a Dumon stent after coring it out using a rigid bronchoscope. Since the patient was a teacher, medical checkups of many people were required, and the number of prophylactic treatments carried out was 80. This was regarded as a mass infection. In the early stages, endobronchial tuberculosis may not show any abnormality on chest radiography, but may still cause mass infection. When a barking cough continues for a long time, endobronchial tuberculosis must be suspected, and examination of a sputum smear for acid-fast bacilli, as well as a sputum culture is necessary.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 09/2003; 41(8):541-5.
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[show abstract]
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ABSTRACT: A 57-year-old man with a 37-year occupational history of welding was admitted for high fever and dyspnea after inhalation of zinc oxide fumes during a period of welding without a protective mask. Chest radiography and CT showed bilateral diffuse ground-glass opacities, and blood gas analysis revealed that PaO2 was 48.1 torr in room air. A transbronchial lung biopsy was done, and revealed diffuse alveolar damage. We diagnosed the case as chemical pneumonia due to the inhalation of zinc oxide, and prescribed prednisolone 40 mg per day. As a result, his symptoms improved within several days. The inhalation of zinc oxide fume usually causes metal fume fever, but chemical pneumonia is also reported on rare occasions. As far as our examination of the literature has disclosed, this is the first report of diffuse alveolar damage after inhalation of zinc oxide fume.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 08/2003; 41(7):447-50.
