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Toru Takahashi,
Seiichi Kobayashi,
Naoya Fujino,
Takaya Suzuki,
Chiharu Ota,
Yukiko Tando,
Mei He,
Mitsuhiro Yamada,
Shin Kurosawa, Mutsuo Yamaya,
Hiroshi Kubo
[show abstract]
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ABSTRACT: ABSTRACT Circulating endothelial microparticles (EMPs) are membrane vesicles that are shed into the blood stream from activated or apoptotic endothelial cells. We previously reported that circulating EMP numbers significantly increased in stable chronic obstructive pulmonary disease (COPD) patients and during exacerbation compared with healthy control subjects. However, different types of circulating EMPs with distinct time profiles were detectable during exacerbations. We hypothesized that the released EMP subtypes correlated with differences in the inflammatory stimuli and the endothelial cell type. We compared the EMP subtypes from human aortic endothelial cells (Aortic ECs) and human lung microvascular endothelial cells (Pulmonary microvascular ECs) released in response to various stimuli, including proinflammatory cytokines (TNFα), oxidative stress (H2O2), and cigarette smoke extracts (CSE) in vitro. We defined circulating EMPs by the expression of endothelial antigens: CD144(+) MPs (VE-cadherin EMPs), CD31(+)/CD41(-) MPs (PECAM EMPs), CD62E(+) MPs (E-selectin EMPs), and CD146(+) MPs (MCAM EMPs). E-selectin EMPs were released from both pulmonary microvascular and aortic ECs in response to TNFα but not to H2O2 or CSE stimulation. The amount of MCAM EMPs released from pulmonary microvascular ECs differed significantly between the cells stimulated with H2O2 and those stimulated with CSE. VE-cadherin EMPs were only released from aortic ECs, whereas PECAM EMPs were released exclusively from pulmonary microvascular ECs. The EMP subtypes released differ in vitro among TNFα, H2O2, and CSE stimulation as well as between pulmonary microvascular and aortic ECs. The differences in circulating EMP subtypes may reflect a condition or site of endothelial injury and may serve as markers for endothelial damage in COPD patients.
Experimental Lung Research 04/2013; · 1.22 Impact Factor
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Naoya Fujino,
Hiroshi Kubo,
Chiharu Ota,
Takaya Suzuki,
Toru Takahashi,
Mitsuhiro Yamada,
Satoshi Suzuki,
Takashi Kondo,
Ryouichi Nagatomi,
Yukiko Tando, Mutsuo Yamaya
The Journal of Infectious Diseases 11/2012; · 6.41 Impact Factor
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Naoya Fujino,
Chiharu Ota,
Takaya Suzuki,
Satoshi Suzuki,
Ahmed E Hegab,
Mitsuhiro Yamada,
Toru Takahashi,
Mei He,
Takashi Kondo,
Hidemasa Kato, Mutsuo Yamaya,
Hiroshi Kubo
[show abstract]
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ABSTRACT: Damage to lung epithelial cells through chronic injury and abnormal repair and remodeling lead to lung destruction and fibrosis. We isolated lung progenitor cells that could potentially contribute to lung diseases. The progenitor cells can differentiate into alveolar type II (ATII)-like cells in vitro, and are increased in number and localized within the region of alveolar epithelial cell proliferation that is involved in the reparative response to injury. However, global gene expression patterns in the ATII-like cells derived from the progenitor cells and in mature ATII cells isolated from lung tissue have not yet been evaluated.
We performed gene expression array and directly compared the gene expression patterns in ATII-like cells derived from the progenitor cells with those in mature ATII cells isolated from human lung tissues.
ATII-like cells and mature ATII cells expressed certain common genes, such as CEPBD and FOXP1, which determine the phenotypes of ATII cells. However, many genes were differentially expressed between the 2 cell types. As compared to mature ATII cells, ATII-like cells showed decreased expression of the genes associated with surfactant protein production and epithelial phenotypes. Pathway analysis indicated changes in several pathways, including those involved in epithelial-to-mesenchymal transition and receptor tyrosine kinase signaling, which could contribute to the observed differences in gene expression patterns.
In this study, we identified genes commonly or differentially expressed by ATII-like cells differentiated from progenitor cells and mature ATII cells isolated from human lung tissues.
Respiratory investigation. 09/2012; 50(3):110-6.
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Toru Takahashi,
Seiichi Kobayashi,
Naoya Fujino,
Takaya Suzuki,
Chiharu Ota,
Mei He,
Mitsuhiro Yamada,
Satoshi Suzuki,
Masaru Yanai,
Shin Kurosawa, Mutsuo Yamaya,
Hiroshi Kubo
[show abstract]
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ABSTRACT: RATIONALE: The influence of COPD exacerbation on the endothelium is not completely understood. Circulating endothelial microparticles (EMPs) are membrane vesicles in circulating blood that are shed by activated or apoptotic endothelial cells. OBJECTIVE: To compare EMP numbers in stable COPD patients with those during and after exacerbation. METHODS: We examined the EMP numbers in 80 stable COPD patients, 27 patients with exacerbated COPD, and 20 healthy non-COPD volunteers. EMPs were defined as CD144+ MPs (VE-cadherin EMPs), CD31+/CD41- MPs (PECAM EMPs), CD146 MPs (MCAM EMPs) and CD62E+ EMPs (E-selectin EMPs) as analysed by FACS. Von Willebrand factor (vWF) expression was utilised to identify the origins of the EMPs. RESULTS: VE-cadherin, PECAM and E-selectin EMP numbers were significantly higher in the stable COPD patients than in the non-COPD volunteers, and they were significantly higher in the patients with exacerbated COPD than in the stable COPD patients. The majority of these increased EMPs were vWF-negative, indicating a pulmonary capillary origin. Baseline E-selectin EMP levels were significantly higher in COPD patients who experienced frequent exacerbations than in those who did not have frequent exacerbations (p<0.001). Twenty-eight days after the onset of exacerbation, E-selectin EMP levels returned to those observed in stable COPD patients, whereas PECAM EMP levels remained high. MCAM EMP numbers were not elevated in stable or exacerbated-COPD patients. CONCLUSIONS: Endothelial damage, mainly in pulmonary capillaries, occurs during exacerbation and continues even after clinical symptoms disappear. Higher baseline E-selectin EMP levels may indicate COPD patients who are susceptible to exacerbation.
Thorax 07/2012; · 6.84 Impact Factor
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ABSTRACT: Respiratory virus infections, including infections with rhinoviruses (RVs), are related to exacerbations of chronic obstructive pulmonary disease (COPD). A new quinolone antibiotic, levofloxacin (LVFX), has been used to treat bacterial infections that cause COPD exacerbations as well as bacterial infections that are secondary to viral infection in COPD patients. However, the inhibitory effects of LVFX on RV infection and RV infection-induced airway inflammation have not been studied. We examined the effects of LVFX on type 14 rhinovirus (RV14) (a major human RV) infection of human tracheal epithelial cells pretreated with LVFX. LVFX pretreatment reduced the RV14 titer, the level of cytokines in the supernatant, the amount of RV14 RNA in the cells after RV14 infection, and the cells' susceptibility to RV14 infection. LVFX pretreatment decreased the mRNA level of intercellular adhesion molecule 1 (ICAM-1), a receptor for RV14, in the cells and the concentration of the soluble form of ICAM-1 in the supernatant before RV14 infection. LVFX pretreatment also decreased the number and the fluorescence intensity of the acidic endosomes from which RV14 RNA enters the cytoplasm. LVFX pretreatment inhibited the activation of nuclear factor κB proteins, including p50 and p65, in nuclear extracts. LVFX pretreatment did not reduce the titers of RV2 (a minor human RV) but reduced the titers of RV15 (a major human RV). These results suggest that LVFX inhibits major-group rhinovirus infections in part by reducing ICAM-1 expression levels and the number of acidic endosomes. LVFX may also modulate airway inflammation in rhinoviral infections.
Antimicrobial Agents and Chemotherapy 05/2012; 56(8):4052-61. · 4.84 Impact Factor
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Hiroki Nagai,
Hiroyasu Yasuda,
Yukimasa Hatachi,
Deng Xue,
Takahiko Sasaki, Mutsuo Yamaya,
Yuichi Sakamori,
Yousuke Togashi,
Katsuhiro Masago,
Isao Ito,
Young Hak Kim,
Tadashi Mio,
Michiaki Mishima
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ABSTRACT: Pemetrexed (PEM) is a novel, multitargeted, antifolate, antineoplastic agent for the treatment of non-small cell lung cancer and malignant pleural mesothelioma. Additional effects of nitric oxide (NO) donors on the chemosensitivity of cancers have been reported. However, the effects of an NO donor on PEM-induced cytotoxicity remain unknown. In this study, we investigated the effects of the NO donors, NOC-18 on the cytotoxicity in A549 cells in vitro and of nitroglycerin (GTN), on the tumor growth of Lewis lung carcinoma cells in a murine syngraft model treated with PEM. The effects of NO donors on the expression of proteins associated with PEM metabolism, including thymidylate synthase (TS), reduced folate carrier 1 (RFC1), folylpolyglutamate synthase (FPGS), γ-glutamyl hydrolase (GGH) and multidrug resistance-related protein (MRP)5, and the effects of cyclic guanosine mono-phosphate (cGMP) signaling on these proteins were examined in A549 cells. Treatment with 100 nM NOC-18 for 3 days significantly enhanced PEM-induced cytotoxicity and increased the expression of RFC1 and FPGS in A549 cells. Treatment with 10 nM 8-bromo-cGMP (8-Br-cGMP) for 3 days also increased the expression of RFC1 and FPGS in A549 cells. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 µm) significantly reversed the increase in RFC1 and FPGS expression induced by 100 nM NOC-18 in A549 cells. Combination therapy with GTN and PEM significantly reduced tumor growth compared with PEM alone in the syngraft model. The enhanced antitumor effect of GTN plus PEM was significantly reversed by the concomitant addition of ODQ. These findings suggest that NO donors, such as NOC-18 and GTN, enhance the anticancer effects of PEM by increasing the RFC1 and FPGS expression and stimulating cGMP signaling pathways in cancer cells.
International Journal of Oncology 05/2012; 41(1):24-30. · 2.40 Impact Factor
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Geriatrics & Gerontology International 04/2012; 12(2):352-3.
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ABSTRACT: The aim of this study was to identify the gene expression pattern specific in alveolar epithelial type II cells (ATII cells) isolated from patients with chronic obstructive pulmonary disease (COPD).
Case control.
Two hospitals in Japan.
Three patients without COPD and three patients with COPD in microarray analyses. Five smokers without COPD and nine smokers with COPD in the following analyses. PRIMARY AND SECONDARY OUTCOME MEASURED: Primary outcome included identification of differentially expressed genes and activated or inhibited pathways in ATII cells of the patients with COPD, compared to those of the patients without COPD, using Affymetrix gene expression arrays. Secondary outcome included validation of the results of microarray analyses by quantitative reverse transcription-PCR.
We isolated ATII cells from COPD and non-COPD lungs using fluorescence-activated cell sorting. We performed Affymetrix gene expression arrays on both types of ATII cells. Gene set enrichment analyses revealed that two major gene sets were enriched in ATII cells from COPD lungs: interferon-responsive gene sets and gene sets associated with cell cycle progression. Gene ontology term enrichment analyses indicated that among the interferon-stimulated genes, ATII cells in COPD expressed genes such as PSMB8, PSMB9, TAP1 and TAP2 associated with the antigen processing and presentation pathway. We validated the results of the microarray analyses using quantitative reverse transcriptase-PCR. In addition, FACS analysis indicated that the percentage of ATII cells to CD45-negative lung cells isolated from COPD lungs were significantly increased more than that from non-COPD lungs.
Our study demonstrated that interferon-stimulated genes involved in the antigen processing and presentation pathway and genes involved in cell cycle progression were enriched in ATII cells of the patients with COPD. These pathways might alter phenotypes of ATII cells in COPD lungs.
BMJ open. 01/2012; 2(6).
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ABSTRACT: Excess production of neutrophil elastase contributes to the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the role of neutrophil elastase in the repair process following ALI/ARDS is not well understood. The objective of this study was to evaluate the effect of neutrophil elastase on the process of tissue repair after acute lung injury in mice. C57BL/6 mice were exposed to sublethal irradiation followed by intranasal instillation of lipopolysaccharide (LPS) to generate a model of impaired lung repair. The authors assessed the histopathology, lung mechanics, and total lung collagen content 7 days after irradiation and/or LPS-induced injury with daily administration of a neutrophil elastase inhibitor. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was also evaluated. In addition, the concentration of activated transforming growth factor (TGF)-β1 in the BALF and the expression of phospho-SMAD2/3 were investigated. Irradiated and LPS-treated mice developed pulmonary fibrosis after injury. The neutrophil elastase inhibitor significantly decreased the collagen deposition in lung parenchyma and improved the static lung compliance of injured lungs. Administration of the neutrophil elastase inhibitor also decreased the accumulation of neutrophils in the BALF, TGF-β1 activation, and expression of phospho-SMAD2/3. The authors conclude that inhibiting neutrophil elastase protects against the development of lung fibrosis after acute injury. In addition, these data suggest that this neutrophil elastase inhibitor has therapeutic potential for the fibroproliferative phase of ALI/ARDS.
Experimental Lung Research 12/2011; 38(1):28-36. · 1.22 Impact Factor
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ABSTRACT: To examine the effects of l-carbocisteine on airway infection with respiratory syncytial (RS) virus, human tracheal epithelial cells were pretreated with l-carbocisteine and infected with RS virus. Viral titer, virus RNA, and pro-inflammatory cytokine secretion, including interleukin (IL)-1 and IL-6, increased with time after infection. l-carbocisteine reduced the viral titer in the supernatant fluids, the amount of RS virus RNA, RS virus infection susceptibility, and the concentration of pro-inflammatory cytokines induced by virus infection. l-carbocisteine reduced the expression of intercellular adhesion molecule (ICAM)-1, an RS virus receptor, on the cells. However, l-carbocisteine had no effects on the expression of heparan sulfate, a glycosaminoglycan that binds to the RS virus attachment protein, or on the amount of intracellular activated-RhoA, isoform A of the Ras-homologous family, that binds to the RS virus fusion protein. These findings suggest that l-carbocisteine may inhibit RS virus infection by reducing the expression of ICAM-1. It may also modulate airway inflammation during RS virus infection.
Respiratory Physiology & Neurobiology 11/2011; 180(1):112-8. · 2.24 Impact Factor
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Naoya Fujino,
Hiroshi Kubo,
Chiharu Ota,
Takaya Suzuki,
Satoshi Suzuki,
Mitsuhiro Yamada,
Toru Takahashi,
Mei He,
Takashi Suzuki,
Takashi Kondo, Mutsuo Yamaya
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ABSTRACT: A variety of lung diseases, such as pulmonary emphysema and idiopathic pulmonary fibrosis, develop in the lung alveoli. Multiple cell types are localized in the alveoli, including epithelial, mesenchymal, and endothelial cells. These resident cells participate in the pathogenesis of lung disease in various ways. To elaborate clearly on the mechanisms of these pathologic processes, cell type-specific analyses of lung disease are required. However, no method exists for individually isolating the different types of cells found in the alveoli. We report on the development of a FACS-based method for the direct isolation of individual cell types from the adult human distal lung. We obtained human lung tissue from lung resections, and prepared single-cell suspension. After depleting CD45-positive cells, a combination of antibodies against epithelial cell adhesion molecule (EpCAM), T1α, and vascular endothelial (VE)-cadherin as used to delineate alveolar cell types. Alveolar Type II cells were highly purified in the EpCAM(hi)/T1α(-) subset, whereas the EpCAM(+)/T1α(-/low) subset contained a mixed epithelial population consisting of alveolar Type I and bronchiolar epithelial cells. The EpCAM(-)/T1α(-) subset included both microvascular endothelial and mesenchymal cells, and these were separated by immunoreactivity to VE-cadherin. Lymphatic endothelial cells existed in the EpCAM(-)/T1α(hi) subset. Isolated cells were viable, and further cell culture studies could be performed. These results suggest that this novel method enables the isolation of different cellular components from normal and diseased lungs, and is capable of elucidating phenotypes specific to certain alveolar cell types indicative of lung disease.
American Journal of Respiratory Cell and Molecular Biology 10/2011; 46(4):422-30. · 5.13 Impact Factor
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Mei He,
Hiroshi Kubo,
Konosuke Morimoto,
Naoya Fujino,
Takaya Suzuki,
Toru Takahasi,
Mitsuhiro Yamada, Mutsuo Yamaya,
Tomoyuki Maekawa,
Yasuhiko Yamamoto,
Hiroshi Yamamoto
[show abstract]
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ABSTRACT: Clearance of apoptotic cells is necessary for tissue development, homeostasis and resolution of inflammation. The uptake of apoptotic cells is initiated by an ‘eat-me’ signal, such as phosphatidylserine, on the cell surface and phagocytes recognize the signal by using specific receptors. In this study, we show that the soluble form of the receptor for advanced glycation end products (RAGE) binds to phosphatidylserine as well as to the apoptotic thymocytes. RAGE-deficient (
EMBO Reports 03/2011; 12(4):358-364. · 7.36 Impact Factor
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ABSTRACT: Recent studies suggest that there is endothelial impairment in both the systemic and pulmonary circulations of patients with COPD. Endothelial progenitor cells (EPC) are mobilized into the circulation by physiological stressors such as surgery, and are thought to play a role in the repair of damaged endothelium. There has been a steady increase in the frequency of surgery among COPD patients, due to the incidence of complications and lung cancer; however, the mobilization of EPC during lung resection has not been examined. We evaluated whether the mobilization and proliferation of EPC are impaired in COPD patients.
The numbers of circulating EPC (CD34/KDR/AC133-positive mononuclear cells) were measured by flow cytometry, in COPD patients (n=30) and non-COPD patients (n=30) who were undergoing thoracic surgery. EPC colony-forming units (EPC-CFU) were also examined.
In non-COPD patients, both circulating EPC and EPC-CFU were significantly increased 2h after the operation started, whereas in COPD patients there were no changes in circulating EPC or EPC-CFU, irrespective of the severity of COPD. Multiple linear regression analysis demonstrated that the presence of COPD was the only significant independent predictor of reduced mobilization of EPC during thoracic surgery.
The number of circulating EPC and EPC-CFU was not increased during thoracic surgery in COPD patients. These results indicate that both the mobilization and proliferative capacity of EPC are severely impaired in COPD patients.
Respirology 03/2011; 16(4):680-7. · 2.42 Impact Factor
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ABSTRACT: Acute exacerbations of chronic obstructive pulmonary disease (COPD), an acute worsening of respiratory symptoms, generally result in a poor prognosis. Successful prevention and management of such exacerbations is thus important for patient care. Viral infection, primarily with rhinovirus (RV), is the foremost cause of exacerbations in COPD patients. Proton pump inhibitors (PPIs) have been reported to inhibit RV infection in human airway epithelial cells in vitro. Furthermore, clinical trials of PPIs in patients with COPD resulted in a reduction in rates of both common cold and COPD exacerbations. In this review, we discuss the significance of COPD exacerbations, summarize a published trial of the effect of low-dose PPIs on COPD exacerbations, and postulate a mechanism for this effect.
Therapeutic Advances in Respiratory Disease 02/2011; 5(2):91-103.
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Naoya Fujino,
Hiroshi Kubo,
Takaya Suzuki,
Chiharu Ota,
Ahmed E Hegab,
Mei He,
Satoshi Suzuki,
Takashi Suzuki,
Mitsuhiro Yamada,
Takashi Kondo,
Hidemasa Kato, Mutsuo Yamaya
[show abstract]
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ABSTRACT: Resident stem/progenitor cells in the lung are important for tissue homeostasis and repair. However, a progenitor population for alveolar type II (ATII) cells in adult human lungs has not been identified. The aim of this study is to isolate progenitor cells from adult human lungs with the ability to differentiate into ATII cells. We isolated colony-forming cells that had the capability for self-renewal and the potential to generate ATII cells in vitro. These undifferentiated progenitor cells expressed surface markers of mesenchymal stem cells (MSCs) and surfactant proteins associated with ATII cells, such as CD90 and pro-surfactant protein-C (pro-SP-C), respectively. Microarray analyses indicated that transcripts associated with lung development were enriched in the pro-SP-C(+)/CD90(+) cells compared with bone marrow-MSCs. Furthermore, pathological evaluation indicated that pro-SP-C and CD90 double-positive cells were present within alveolar walls in normal lungs, and significantly increased in ATII cell hyperplasias contributing to alveolar epithelial repair in damaged lungs. Our findings demonstrated that adult human lungs contain a progenitor population for ATII cells. This study is a first step toward better understanding of stem cell biology in adult human lung alveoli.
Laboratory Investigation 11/2010; 91(3):363-78. · 3.64 Impact Factor
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Mutsuo Yamaya,
Hidekazu Nishimura,
Yukimasa Hatachi,
Motoki Yoshida,
Hidenori Fujiwara,
Masanori Asada,
Katsutoshi Nakayama,
Hiroyasu Yasuda,
Xue Deng,
Takahiko Sasaki,
Hiroshi Kubo,
Ryoichi Nagatomi
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ABSTRACT: β(2) agonists reduce the frequency of exacerbations in patients with bronchial asthma and chronic obstructive pulmonary disease caused by respiratory virus infection. β(2) agonists reduce the production of pro-inflammatory cytokines. However, the inhibitory effects of β(2) agonists on the infection of rhinovirus, the major cause of exacerbations, have not been well studied. To examine the effects of a β(2) agonist, procaterol, on rhinovirus infection and rhinovirus infection-induced airway inflammation, human tracheal epithelial cells were infected with a major group rhinovirus, type 14 rhinovirus. Rhinovirus infection increased viral titers and the content of pro-inflammatory cytokines, including interleukin-1β and interlukin-6, in supernatant fluids and rhinovirus RNA in the cells. Procaterol reduced rhinovirus titers and RNA, cytokine concentrations, and susceptibility to rhinovirus infection. Procaterol reduced the expression of intercellular adhesion molecule-1 (ICAM-1), the receptor for type 14 rhinovirus, and the number of acidic endosomes in the cells from which rhinovirus RNA enters into the cytoplasm. Procaterol inhibited the activation of nuclear factor kappa-B (NF-κB) proteins including p50 and p65 in the nuclear extracts, while it increased the cytosolic amount of the inhibitory kappa B-α and intracellular cyclic AMP (cAMP) levels. A selective β(2)-adrenergic receptor antagonist ICI 118551 [erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol] reversed the inhibitory effects of procaterol on rhinovirus titers and RNA, susceptibility to rhinovirus infection, pro-inflammatory cytokines production, ICAM-1 expression, acidic endosomes, and NF-κB. ICI 118551 also reversed the effects of procaterol on cAMP levels. Procaterol may inhibit rhinovirus infection by reducing ICAM-1 and acidic endosomes as well as modulate airway inflammation in rhinovirus infection.
European journal of pharmacology 10/2010; 650(1):431-44. · 2.59 Impact Factor
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Mutsuo Yamaya,
Hidekazu Nishimura,
Kyoko Shinya,
Yukimasa Hatachi,
Takahiko Sasaki,
Hiroyasu Yasuda,
Motoki Yoshida,
Masanori Asada,
Naoya Fujino,
Takaya Suzuki,
Xue Deng,
Hiroshi Kubo,
Ryoichi Nagatomi
[show abstract]
[hide abstract]
ABSTRACT: Type A human seasonal influenza (FluA) virus infection causes exacerbations of bronchial asthma and chronic obstructive pulmonary disease (COPD). l-carbocisteine, a mucolytic agent, reduces the frequency of common colds and exacerbations in COPD. However, the inhibitory effects of l-carbocisteine on FluA virus infection are uncertain. We studied the effects of l-carbocisteine on FluA virus infection in airway epithelial cells. Human tracheal epithelial cells were pretreated with l-carbocisteine and infected with FluA virus (H(3)N(2)). Viral titers in supernatant fluids, RNA of FluA virus in the cells, and concentrations of proinflammatory cytokines in supernatant fluids, including IL-6, increased with time after infection. l-carbocisteine reduced viral titers in supernatant fluids, RNA of FluA virus in the cells, the susceptibility to FluA virus infection, and concentrations of cytokines induced by virus infection. The epithelial cells expressed sialic acid with an alpha2,6-linkage (SAalpha2,6Gal), a receptor for human influenza virus on the cells, and l-carbocisteine reduced the expression of SAalpha2,6Gal. l-carbocisteine reduced the number of acidic endosomes from which FluA viral RNA enters into the cytoplasm and reduced the fluorescence intensity from acidic endosomes. Furthermore, l-carbocisteine reduced NF-kappaB proteins including p50 and p65 in the nuclear extracts of the cells. These findings suggest that l-carbocisteine may inhibit FluA virus infection, partly through the reduced expression of the receptor for human influenza virus in the human airway epithelial cells via the inhibition of NF-kappaB and through increasing pH in endosomes. l-carbocisteine may reduce airway inflammation in influenza virus infection.
AJP Lung Cellular and Molecular Physiology 08/2010; 299(2):L160-8. · 3.66 Impact Factor
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ABSTRACT: Human influenza viruses attach to sialic acid with an alpha2,6linkage (SAalpha2,6Gal) on the airway epithelial cells, and the entry of the viruses into the cells and uncoating of the viruses require low pH of endosomes. Bafilomycin A(1), a macrolide antibiotic and a specific inhibitor of vacuolar H(+)-ATPase, inhibits growth of type A and type B human influenza viruses in Madin-Darby canine kidney cells. However, the inhibitory effects of clinically used macrolide antibiotics on influenza virus infection in human airways have not been studied. To examine the effects of clarithromycin on seasonal human influenza virus infection, cultured human tracheal epithelial cells were infected with type A influenza virus (H3N2). Influenza virus infection increased viral titers and the content of cytokines, including interleukin (IL)-1beta and IL-6, in supernatant fluids, and viral RNA in the cells. Clarithromycin reduced viral titers and the content of cytokines in supernatant fluids, viral RNA in the cells, and the susceptibility to virus infection. Clarithromycin reduced the expression of SAalpha2,6Gal, a receptor for human influenza virus, on the mucosal surface of human tracheae, and the number and fluorescence intensity of acidic endosomes in the cells from which viral ribonucleoproteins enter into the cytoplasm. Furthermore, clarithromycin reduced nuclear factor-kappaB (NF-kappaB) proteins, including p50 and p65, in the nuclear extracts. These results suggest that clarithromycin may inhibit seasonal human influenza virus infection by reducing SAalpha2,6Gal partly through the inhibition of NF-kappaB, and increasing pH in endosomes in airway epithelial cells. Clarithromycin may modulate airway inflammation in influenza virus infection.
Journal of Pharmacology and Experimental Therapeutics 04/2010; 333(1):81-90. · 3.83 Impact Factor
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ABSTRACT: In cancer science, nitric oxide (NO) has been mainly discussed as an oncogenic molecule over the past decades. However, NO
has recently been noted in cancer biology to be associated with cancer cell apoptosis, cancer cell cycle, cancer progression
and metastasis, cancer angiogenesis, cancer chemoprevention, and a modulator for chemo/radio/immunotherapy. NO is produced
and released from three different isoforms of NO synthase (NOS) and from exogenously administered NO donors in vivo. Over-expression
of inducible NOS (iNOS) in cancer tissues is associated with an increase in microvascular density in tumor tissues and poor
prognosis in patients with cancers. Recently, NO donors and iNOS transfer have been demonstrated to enhance the effects of
cancer therapy including chemotherapy, radiotherapy, and immunotherapy for solid cancers, resulting in a prolonged survival
time. In this chapter, we to discuss the recent animal experiments and clinical trials to develop these investigations for
clinical applications.
KeywordsNitric oxide-Nitric oxide synthase-Cancer biology-Cancer progression-Metastasis-Apoptosis-Cell cycle-Proliferation-Chemoprevention-Chemotherapy-Radiotherapy-Immunotherapy-Animal experiment-Clinical trial
12/2009: pages 419-441;
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ABSTRACT: The capacity of the lung to repair itself after injury is well known, but the cell types involved in lung regeneration remain undefined. The aim of this study was to isolate and characterize resident progenitor/stem cells from adult mouse lung. We report the isolation and characterization of resident stem cells that have a Sca1+/CD45(-)/CD31(-) phenotype. Their immunophenotype and differentiative potentiality were distinct from that of other previously described lung stem cells. These cells underwent extensive self-renewal in culture and could differentiate into endothelial and lung epithelial (alveolar type I, II, and Clara) cells in vitro. They have exhibited some mesenchymal but no neural differentiation ability. Transfer of these cells into mouse models of lung injury significantly improved survival and minimized lung destruction. These cells may provide useful tools for the study of lung stem cells and the assessment of new therapeutic approaches for lung diseases.
Stem cells and development 10/2009; 19(4):523-36. · 4.15 Impact Factor
