32 results on '"Takumi Kiwamoto"'
Search Results
2. Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice
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Mingma Thsering Sherpa, Takumi Kiwamoto, Masashi Matsuyama, Yoshiya Tsunoda, Kai Yazaki, Kazufumi Yoshida, Masayuki Nakajima, Yosuke Matsuno, Yuko Morishima, Yukio Ishii, and Nobuyuki Hizawa
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endocrine system ,mouse model ,Immunology ,respiratory system ,asthma ,RC581-607 ,ER stress response ,IL-17 ,airway remodeling ,HAS2 ,TGF-β1 ,Immunology and Allergy ,Immunologic diseases. Allergy ,Original Research - Abstract
HAS2 is a member of the gene family encoding the hyaluronan synthase 2, which can generate high-molecular-weight hyaluronan (HMW-HA). Our previous study identified HAS2 as a candidate gene for increased susceptibility to adult asthma. However, whether HAS2 dysfunction affects airway remodeling and steroid insensitivity is still limited. Therefore, this study aimed to clarify the Has2 dysfunction, triggering severe airway remodeling and steroid insensitivity in a murine model of asthma. Has2 heterozygous-deficient (Has2+/−) mice and their wild-type littermates have been evaluated in a model of chronic ovalbumin (OVA) sensitization and challenge. Mice present a higher sensitivity to OVA and higher IL-17 release as well as eosinophilic infiltration. RNA sequencing demonstrated the downregulation of EIF2 signaling pathways, TGF-β signaling pathways, and heat shock proteins with Th17 bias in Has2+/−-OVA mice. The combined treatment with anti-IL-17A antibody and dexamethasone reduces steroid insensitivity in Has2+/−-OVA mice. Has2 attenuation worsens eosinophilic airway inflammation, airway remodeling, and steroid insensitivity. These data highlight that HAS2 and HMW-HA are important for controlling intractable eosinophilic airway inflammation and remodeling and could potentially be exploited for their therapeutic benefits in patients with asthma.
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- 2022
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3. ELOVL6 deficiency aggravates allergic airway inflammation through the ceramide-S1P pathway in mice
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Kazufumi Yoshida, Yuko Morishima, Satoshi Ano, Hirofumi Sakurai, Kenya Kuramoto, Yoshiya Tsunoda, Kai Yazaki, Masayuki Nakajima, Mingma Thering Sherpa, Masashi Matsuyama, Takumi Kiwamoto, Yosuke Matsuno, Yukio Ishii, Akio Hayashi, Takashi Matsuzaka, Hitoshi Shimano, and Nobuyuki Hizawa
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Immunology ,Immunology and Allergy - Abstract
Elongation of very-long-chain fatty acids protein 6 (ELOVL6), an enzyme regulating elongation of saturated and monounsaturated fatty acids with C12-C16 to those with C18, has been recently indicated to affect various immune and inflammatory responses; however, the precise process by which ELOVL6-related lipid dysregulation affects allergic airway inflammation is unclear.To evaluate the biological roles of ELOVL6 in allergic airway responses and investigate whether regulating lipid composition in the airways could be an alternative treatment for asthma.Expressions of ELOVL6 and other isoforms were examined in the airways of severely asthmatic patients and mouse models of asthma. Wild-type (WT) and ELOVL6-deficient (Elovl6ELOVL6 expression was downregulated in the bronchial epithelium of severely asthmatic patients compared with controls. In asthmatic mice, ELOVL6 deficiency led to enhanced airway inflammation in which lymphocyte egress from lymph nodes was increased, and both type 2 and non-type 2 immune responses were upregulated. Lipidomic profiling revealed that the levels of palmitic acid, ceramides and sphingosine-1-phosphate (S1P) were higher in the lungs of OVA-immunized Elovl6This study illustrates a crucial role for ELOVL6 in controlling allergic airway inflammation via regulation of fatty acid composition and ceramide-S1P biosynthesis, and indicates that ELOVL6 may be a novel therapeutic target for asthma.
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- 2021
4. Depletion of PD-1 or PD-L1 did not affect the mortality of mice infected with Mycobacterium avium
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Takumi Kiwamoto, Yuko Morishima, Ryota Tanaka, Mio Kawaguchi, Yukio Ishii, Kazufumi Yoshida, Masafumi Muratani, Masashi Matsuyama, Sosuke Matsumura, Masayuki Nakajima, Nobuyuki Hizawa, Yosuke Matsuno, Kai Yazaki, Mingma Thsering Sherpa, and Naoko Okiyama
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Genotype ,Science ,T cell ,Immunology ,Programmed Cell Death 1 Receptor ,Cell ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,Microbiology ,Article ,B7-H1 Antigen ,Mycobacterium tuberculosis ,Transcriptome ,Mice ,Immune system ,Cell Movement ,PD-L1 ,medicine ,Animals ,Tuberculosis ,Lung ,Mice, Knockout ,Multidisciplinary ,Gene Expression Profiling ,Th1 Cells ,biology.organism_classification ,Survival Analysis ,Chemokine activity ,medicine.anatomical_structure ,Gene Expression Regulation ,biology.protein ,Medicine ,Female ,Infection ,Mycobacterium avium ,Mycobacterium - Abstract
The programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) pathway could affect antimicrobial immune responses by suppressing T cell activity. Several recent studies demonstrated that blocking of the PD-1/PD-L1 pathway exacerbated Mycobacterium tuberculosis infection. However, the effect of blocking this pathway in pulmonary Mycobacterium avium–intracellulare complex (MAC) infection is not fully understood. Wild-type, PD-1-deficient mice, and PD-L1-deficient mice were intranasally infected with Mycobacterium avium bacteria. Depletion of PD-1 or PD-L1 did not affect mortality and bacterial burden in MAC-infected mice. However, marked infiltration of CD8-positive T lymphocytes was observed in the lungs of PD-1 and PD-L1-deficient mice compared to wild-type mice. Comprehensive transcriptome analysis showed that levels of gene expressions related to Th1 immunity did not differ according to the genotypes. However, genes related to the activity of CD8-positive T cells and related chemokine activity were upregulated in the infected lungs of PD-1 and PD-L1-deficient mice. Thus, the lack of change in susceptibility to MAC infection in PD-1 and PD-L1-deficient mice might be explained by the absence of obvious changes in the Th1 immune response. Furthermore, activated CD8-positive cells in response to MAC infection in these mice seemed to not be relevant in the control of MAC infection.
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- 2021
5. Transcription Factor T-bet Attenuates the Development of Elastase-induced Emphysema in Mice
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Hirofumi Sakurai, Satoru Takahashi, Takumi Kiwamoto, Keigyou Yoh, Yukio Ishii, Yuko Morishima, Shigen Hayashi, Yosuke Matsuno, Yoshiya Tsunoda, and Nobuyuki Hizawa
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CD4-Positive T-Lymphocytes ,0301 basic medicine ,Neutrophils ,Clinical Biochemistry ,Adaptive Immunity ,Pathogenesis ,Mice ,0302 clinical medicine ,Medicine ,RNA, Small Interfering ,Lung ,Mice, Knockout ,Mice, Inbred BALB C ,Pancreatic Elastase ,biology ,Elastase ,Nuclear Receptor Subfamily 1, Group F, Member 1 ,hemic and immune systems ,respiratory system ,Chemotaxis, Leukocyte ,Phenotype ,medicine.anatomical_structure ,Pulmonary Emphysema ,Cytokines ,Female ,RNA Interference ,Interleukin 17 ,medicine.symptom ,Bronchoalveolar Lavage Fluid ,Pulmonary and Respiratory Medicine ,chemical and pharmacologic phenomena ,Inflammation ,Alveolar cells ,03 medical and health sciences ,Immune system ,Animals ,Interleukin 6 ,Molecular Biology ,business.industry ,Macrophages ,Editorials ,Cell Biology ,Immunity, Innate ,Lymphocyte Subsets ,respiratory tract diseases ,030104 developmental biology ,030228 respiratory system ,Immunology ,biology.protein ,T-Box Domain Proteins ,business - Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by peripheral airways inflammation and emphysema. Emerging evidence indicates a contribution of both innate and adaptive immune cells to the development of COPD. Transcription factor T-bet modulates the function of immune cells and therefore might be involved in the pathogenesis of COPD. To elucidate the role for T-bet in elastase-induced emphysema, pathological phenotypes were compared between wild-type and T-bet-/- mice. T-bet-/- mice demonstrated enhanced emphysema development on histological analyses, with higher values of mean linear intercept and dynamic compliance relative to wild-type mice. The number of neutrophils in BAL fluids, lung IL-6 and IL-17 expression, and the proportion of CD4+ T cells positive for IL-17 or retinoic acid receptor-related orphan receptor-γt were higher in T-bet-/- mice than in wild-type mice. Although T-bet downregulates cytokine expression in bone marrow-derived macrophages and MH-S cells, a murine alveolar cell line, depending on the surrounding environment, IL-6 expression in alveolar macrophages isolated from elastase-treated mice was not dependent on T-bet. Coculture of bone marrow-derived macrophages and CD4+ T cells revealed that T-bet regulation of IL-17 expression was dependent on CD4+ T cells. Neutralizing antibodies against IL-6R or IL-17 ameliorated the development of emphysema in T-bet-/- mice. In conclusion, we demonstrate that T-bet ameliorates elastase-induced emphysema formation by modulating the host immune response in the lungs.
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- 2019
6. Has2 deficiency enhances OVA-induced airway inflammation and hyperresponsiveness in mice
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Masashi Matsuyama, Nobuyuki Hizawa, Hirofumi Sakurai, Yukio Ishii, Yuko Morishima, Takumi Kiwamoto, Hajime Osawa, Yosuke Matsuno, Yoshiya Tsunoda, Mingma Thsering Sherpa, and Shigen Hayashi
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Inflammation ,Mice, Inbred BALB C ,biology ,business.industry ,Ovalbumin ,Immunology ,Airway hyperresponsiveness ,CD44 ,Respiratory System ,Airway inflammation ,Disease Models, Animal ,Mice ,biology.protein ,Immunology and Allergy ,Medicine ,Animals ,Bronchial Hyperreactivity ,business ,Bronchoalveolar Lavage Fluid ,Lung - Published
- 2020
7. Clinical significance of invariant natural killer T cells and IL-5 in acute eosinophilic pneumonia
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Yukio Ishii, Yuko Morishima, Kazufumi Yoshida, Yosuke Matsuno, Masashi Matsuyama, Nobuyuki Hizawa, and Takumi Kiwamoto
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lcsh:Immunologic diseases. Allergy ,Adult ,Male ,Adolescent ,government.form_of_government ,Young Adult ,Text mining ,Immunology and Allergy ,Medicine ,Humans ,Clinical significance ,Pulmonary Eosinophilia ,Interleukin 5 ,Invariant natural killer T-cell ,Lung ,Aged ,Aged, 80 and over ,business.industry ,General Medicine ,Middle Aged ,Acute eosinophilic pneumonia ,Immunology ,Acute Disease ,government ,Natural Killer T-Cells ,Female ,Interleukin-5 ,lcsh:RC581-607 ,business ,Bronchoalveolar Lavage Fluid - Published
- 2020
8. Hyaluronan Synthase 2 (HAS2) Mediates Elastase-Induced Airway Inflammation and Emphysema in Mice
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Yuko Morishima, Takumi Kiwamoto, Kazufumi Yoshida, Yoshiya Tsunoda, Kai Yazaki, Yukio Ishii, Masashi Matsuyama, Hajime Osawa, Mingma Thsering Sherpa, Nobuyuki Hizawa, Masayuki Nakajima, and Yosuke Matsuno
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Chemistry ,Elastase ,Immunology ,Airway inflammation ,Hyaluronan Synthase 2 - Published
- 2020
9. Enhanced Type 2 and Non-Type 2 Allergic Airway Inflammation in Elovl6-Deficient Mice
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Kai Yazaki, Masashi Matsuyama, Yuko Morishima, Hajime Osawa, Yosuke Matsuno, Yukio Ishii, Hirofumi Sakurai, Mingma Thsering Sherpa, Nobuyuki Hizawa, Masayuki Nakajima, Takumi Kiwamoto, and Kazufumi Yoshida
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Allergic airway inflammation ,business.industry ,Immunology ,Deficient mouse ,Medicine ,business - Published
- 2020
10. Deletion of Elovl6 Alters Fatty Acid Composition in Lung Tissue and Enhances Allergic Airway Inflammation
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Yuko Morishima, Mingma Thsering Sherpa, Masashi Matsuyama, Yukio Ishii, Yosuke Matsuno, Hideyuki Sakurai, Nobuyuki Hizawa, Masayuki Nakajima, Kazufumi Yoshida, Yoshiya Tsunoda, and Takumi Kiwamoto
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Allergic airway inflammation ,business.industry ,Immunology ,Medicine ,Fatty acid composition ,business ,Lung tissue - Published
- 2019
11. Hyaluronan Synthase 2 (HAS2) Mediates Airway Inflammation and Remodeling in Chronic Ovalbumin Model of Asthma
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Yuko Morishima, Mingma Thsering Sherpa, Kazufumi Yoshida, Yoshiya Tsunoda, Yukio Ishii, Nobuyuki Hizawa, Masayuki Nakajima, Takumi Kiwamoto, Yosuke Matsuno, Hajime Osawa, and Masashi Matsuyama
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Ovalbumin ,biology ,business.industry ,Immunology ,Airway inflammation ,medicine ,biology.protein ,medicine.disease ,Hyaluronan Synthase 2 ,business ,Asthma - Published
- 2019
12. The role of lung epithelial ligands for Siglec-8 and Siglec-F in eosinophilic inflammation
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Toshihiko Katoh, Bruce S. Bochner, Michael Tiemeyer, and Takumi Kiwamoto
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Glycan ,Immunology ,Antigens, Differentiation, Myelomonocytic ,Ligands ,Article ,Mice ,Antigen ,Antigens, CD ,Lectins ,medicine ,Animals ,Humans ,Immunology and Allergy ,Lung ,Sialic Acid Binding Immunoglobulin-like Lectins ,biology ,Inhibitory receptors ,SIGLEC ,respiratory system ,Asthma ,Transmembrane protein ,Cell biology ,Antigens, Differentiation, B-Lymphocyte ,Eosinophils ,medicine.anatomical_structure ,Eosinophilic inflammation ,Apoptosis ,biology.protein - Abstract
Siglec-8 and Siglec-F are single pass transmembrane inhibitory receptors found on the surface of human and mouse eosinophils, respectively, but very little is known about their physiologic glycan ligands. This article reviews the latest knowledge on this topic and outlines the strategies being used to further define the production and glycobiochemical nature of these molecules in the lung.Both Siglec-8 and Siglec-F recognize the same glycan structure, namely 6'-sulfated sialyl Lewis X, as determined using glycan array technologies. Studies have identified α2,3-linked sialylated glycoprotein structures localized to mouse airway epithelium in tissue sections, where their constitutive expression requires the specific sialyltransferase St3gal3. Expression of these ligands in lung is enhanced during allergic inflammation and by cytokines such as IL-13, and is maintained in primary air-liquid interface cultures of mouse lung epithelium. Further characterization suggests that they are high molecular weight sialylated proteins, putatively mucins. By combining analytic glycomics, glycoproteomic mapping, and further in-vitro eosinophil experimentation including the ability of candidate structures to enhance eosinophil apoptosis, a finely detailed appreciation of the structural requirements for productive Siglec-8 and Siglec-F engagement should soon emerge.An enhanced understanding of Siglec-F, Siglec-8, and their ligands should improve our understanding of endogenous lung pathways limiting the survival of eosinophils within the airway in diseases such as asthma. Knowledge of this biology may also result in novel opportunities for drug development involving glycans and glycomimetics that selectively bind to Siglec-8 and induce eosinophil death.
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- 2013
13. Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions
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James C. Paulson, Bruce S. Bochner, Takumi Kiwamoto, and Norihito Kawasaki
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Immunoglobulin gene ,medicine.drug_class ,Antigens, Differentiation, Myelomonocytic ,Monoclonal antibody ,Article ,Immune system ,Antigens, CD ,Polysaccharides ,Lectins ,Eosinophilia ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Mast Cells ,Molecular Targeted Therapy ,Sialic Acid Binding Immunoglobulin-like Lectins ,Pharmacology ,biology ,Antibodies, Monoclonal ,SIGLEC ,respiratory system ,Eosinophil ,Mast cell ,Antigens, Differentiation, B-Lymphocyte ,Eosinophils ,medicine.anatomical_structure ,Immunology ,biology.protein ,Nanoparticles ,Antibody ,medicine.symptom ,Mastocytosis - Abstract
Siglecs (sialic acid immunoglobulin-like lectins) are members of the immunoglobulin gene family that contain sialoside binding N-terminal domains. They are cell surface proteins found predominantly on cells of the immune system. Among them, Siglec-8 is uniquely expressed by human eosinophils and mast cells, as well as basophils. Engaging this structure with antibodies or glycan ligands results in apoptosis in human eosinophils and inhibition of release of preformed and newly generated mediators from human mast cells without affecting their survival. Pro-apoptotic effects are also seen when its closest functional paralog, Siglec-F, on mouse eosinophils is similarly engaged in vitro, and beneficial effects are observed after administration of Siglec-F antibody using models of eosinophilic pulmonary and gastrointestinal inflammation in vivo. Siglec-8 targeting may thus provide a means to specifically inhibit or deplete these cell types. Cell-directed therapies are increasingly sought after by the pharmaceutical industry for their potential to reduce side effects and increase safety. The challenge is to identify suitable targets on the cell type of interest, and selectively deliver a therapeutic agent. By targeting Siglec-8, monoclonal antibodies and glycan ligand-conjugated nanoparticles may be ideally suited for treatment of eosinophil and mast cell-related diseases, such as asthma, chronic rhinosinusitis, chronic urticaria, hypereosinophilic syndromes, mast cell and eosinophil malignancies and eosinophilic gastrointestinal disorders.
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- 2012
14. Blockade of cysteinyl leukotriene-1 receptors suppresses airway remodelling in mice overexpressing GATA-3
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Tohru Sakamoto, Yuko Morishima, Mio Kawaguchi, Norihiro Kikuchi, Satoru Takahashi, Akihiro Nomura, Yukio Ishii, Norihiro Haraguchi, Nobuyuki Hizawa, Keigyou Yoh, Hironori Masuko, and Takumi Kiwamoto
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Genetically modified mouse ,medicine.medical_specialty ,Leukotriene ,Leukotriene receptor ,medicine.medical_treatment ,Immunology ,Inflammation ,respiratory system ,Biology ,respiratory tract diseases ,Cytokine ,Endocrinology ,Eicosanoid ,Internal medicine ,medicine ,Immunology and Allergy ,medicine.symptom ,Receptor ,Montelukast ,medicine.drug - Abstract
Summary Background We demonstrated previously that GATA-3 overexpression markedly enhanced allergen-induced airway inflammation and airway remodelling, including subepithelial fibrosis, and smooth muscle cell hyperplasia, in transgenic mice. Objective Because cysteinyl leukotrienes (cysLTs) have been shown to be involved in such structural changes, the effects of a specific cysLT1 receptor antagonist, montelukast, were evaluated in a mouse model of chronic asthma. Methods GATA-3-overexpressing mice and wild-type Balb/c mice were sensitized and repeatedly challenged by ovalbumin (OVA) or saline. The effects of montelukast on the development of airway remodelling were compared between the two mouse genotypes. Results CysLTs in the lung were increased after repeated allergen challenges, and significantly enhanced in GATA-3-overexpressing mice. The enhanced cysLT levels were accompanied by the development of eosinophilia, smooth muscle cell hyperplasia, and increased stromal cell-derived factor-1 gene expression with a small increase in pro-collagen gene expression in OVA-challenged GATA-3-overexpressing mice, but not in wild-type mice. Montelukast significantly decreased lung cysLT levels and inhibited the GATA-3-overexpression-related airway remodelling, potently preventing smooth muscle cell hyperplasia, but partially suppressed the increased pro-collagen gene expression and eosinophilic inflammation. Increases in the levels of IL-4, IL-5, IL-13, and eotaxin in bronchial lavage and TGF-β gene expression in the lungs were induced by OVA in both mouse genotypes. Montelukast treatment also significantly reduced these levels to the levels seen after saline challenges in GATA-3-overexpressing mice. Conclusion Montelukast efficaciously prevented airway inflammation and remodelling in a GATA-3-overexpression antigen challenge mouse model by decreasing the cysLT-driven Th2 cytokine cycle of amplification of airway pathologies. Cite this as: T. Kiwamoto, Y. Ishii, Y. Morishima, K. Yoh, N. Kikuchi, N. Haraguchi, H. Masuko, M. Kawaguchi, A. Nomura, T. Sakamoto, S. Takahashi and N. Hizawa, Clinical & Experimental Allergy, 2011 (41) 116–128.
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- 2010
15. Overexpression of GATA-3 Protects against the Development of Hypersensitivity Pneumonitis
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Keigyou Yoh, Satoru Takahashi, Shinsuke Homma, Tohru Sakamoto, Norihiro Kikuchi, Yosuke Matsuno, Akihiro Nomura, Yuko Morishima, Takumi Kiwamoto, Morio Ohtsuka, Nobuyuki Hizawa, Takashi Iizuka, Norihiro Haraguchi, and Yukio Ishii
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Pulmonary and Respiratory Medicine ,medicine.medical_treatment ,Mice, Transgenic ,Inflammation ,GATA3 Transcription Factor ,Critical Care and Intensive Care Medicine ,Pathogenesis ,Interferon-gamma ,Mice ,Antigen ,Interferon ,Intensive care ,Animals ,Medicine ,Saccharopolyspora rectivirgula ,RNA, Messenger ,biology ,Tumor Necrosis Factor-alpha ,business.industry ,Interleukins ,medicine.disease ,biology.organism_classification ,Mice, Inbred C57BL ,Disease Models, Animal ,Cytokine ,Immunology ,medicine.symptom ,T-Box Domain Proteins ,business ,Hypersensitivity pneumonitis ,Alveolitis, Extrinsic Allergic ,Saccharopolyspora ,medicine.drug - Abstract
Hypersensitivity pneumonitis (HP) is mediated by a Th1 immune response. Transcription factor GATA binding protein-3 (GATA-3) is believed to be a key regulator of Th2 differentiation and thus might play regulatory roles in the pathogenesis of hypersensitivity pneumonitis (HP).We examined the effect of GATA-3 overexpression on the development of HP in mice.Wild-type C57BL/6 mice and GATA-3-overexpressing mice of the same background were used in this study. HP was induced by repeated exposure to Saccharopolyspora rectivirgula, the causative antigen of farmer's lung.Antigen exposure resulted in a marked inflammatory response with enhanced pulmonary expression of T-bet and the Th1 cytokine interferon (IFN)-gamma in wild-type mice. The degree of pulmonary inflammation was much less severe in GATA-3-overexpressing mice. The induction of T-bet and IFN-gamma genes was suppressed, but a significant induction of Th2 cytokines, including IL-5 and IL-13, was observed in the lungs of GATA-3-overexpressing mice after antigen exposure. Supplementation with recombinant IFN-gamma enhanced lung inflammatory responses in GATA-3-overexpressing mice to the level of wild-type mice. Because antigen-induced IFN-gamma production predominantly occurred in CD4+ T cells, nude mice were transferred with CD4+ T cells from either wild-type or GATA-3-overexpressing mice and subsequently exposed to antigen. Lung inflammatory responses were significantly lower in nude mice transferred with CD4+ T cells from GATA-3-overexpressing mice than in those with wild-type CD4+ T cells, with a reduction of lung IFN-gamma level.These results indicate that overexpression of GATA-3 attenuates the development of HP by correcting the Th1-polarizing condition.
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- 2007
16. Transcription Factor Nrf2 Plays a Pivotal Role in Protection against Elastase-Induced Pulmonary Inflammation and Emphysema
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Ken Itoh, Toru Kimura, Masayuki Yamamoto, Yuko Morishima, Akihiro Nomura, Takumi Kiwamoto, Kiyohisa Sekizawa, Takashi Iizuka, Tohru Sakamoto, Yukio Ishii, Tomonori Hosoya, and Ahmed E. Hegab
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NF-E2-Related Factor 2 ,Immunology ,Gene Expression ,Inflammation ,Oxidative phosphorylation ,Biology ,medicine.disease_cause ,digestive system ,environment and public health ,Antioxidants ,Pathogenesis ,Mice ,medicine ,Animals ,Immunology and Allergy ,Protease Inhibitors ,Lung ,Bone Marrow Transplantation ,Emphysema ,Mice, Knockout ,Mice, Inbred BALB C ,Pancreatic Elastase ,Elastase ,Pneumonia ,respiratory system ,respiratory tract diseases ,Transplantation ,medicine.anatomical_structure ,Bone marrow ,medicine.symptom ,Oxidative stress - Abstract
Emphysema is one of the major pathological abnormalities associated with chronic obstructive pulmonary disease. The protease/antiprotease imbalance and inflammation resulting from oxidative stress have been attributed to the pathogenesis of emphysema. Nrf2 is believed to protect against oxidative tissue damage through the transcriptional activation of a battery of antioxidant enzymes. In this study, we investigated the protective role of Nrf2 in the development of emphysema using elastase-induced emphysema as our model system. We found that elastase-provoked emphysema was markedly exacerbated in Nrf2-knockout (KO) mice compared with wild-type mice. The severity of emphysema in Nrf2-KO mice correlated intimately with the degree of lung inflammation in the initial stage of elastase treatment. The highly inducible expression of antioxidant and antiprotease genes observed in wild-type alveolar macrophages was significantly attenuated in the lungs of Nrf2-KO mice. Interestingly, transplantation of wild-type bone marrow cells into Nrf2-KO mice retarded the development of initial lung inflammation and subsequent emphysema, and this improvement correlated well with the appearance of macrophages expressing Nrf2-regulated antiprotease and antioxidant genes. Thus, Nrf2 appears to exert its protective effects through the transcriptional activation of antiprotease and antioxidant genes in alveolar macrophages.
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- 2005
17. Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema
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Toru Kimura, Kiyohisa Sekizawa, Masayuki Yamamoto, Masako Shimura, Yosuke Matsuno, Akihiro Nomura, Yukio Ishii, Aruto Yoshida, Ahmed E. Hegab, Shinsuke Homma, Yuko Morishima, Ken Itoh, Takumi Kiwamoto, Tohru Sakamoto, and Takashi Iizuka
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Protease ,biology ,medicine.diagnostic_test ,Phagocytosis ,medicine.medical_treatment ,Inflammation ,Cell Biology ,respiratory system ,medicine.disease_cause ,digestive system ,environment and public health ,Pathogenesis ,Bronchoalveolar lavage ,Neutrophil elastase ,Immunology ,Genetics ,biology.protein ,medicine ,medicine.symptom ,Oxidative stress ,SLPI - Abstract
Inflammation, protease/anti-protease imbalance and oxidative stress play important roles in the pathogenesis of emphysema. Nrf2 counteracts oxidative tissue damage and inflammation through transcriptional activation via the anti-oxidant responsive element (ARE). To clarify the protective role of Nrf2 in the development of emphysema, the susceptibility of Nrf2-knockout mice to cigarette smoke (CS)-induced emphysema was examined. In Nrf2-knockout mice, emphysema was first observed at 8 weeks and exacerbated by 16 weeks following CS-exposure, whereas no pathological abnormalities were observed in wild-type mice. Neutrophilic lung inflammation and permeability lung damage were significantly enhanced in Nrf2-knockout mice 8 weeks after CS-exposure. Importantly, neutrophil elastase activity in bronchoalveolar lavage fluids was markedly higher in Nrf2-knockout mice preceding the pronounced neutrophil accumulation. The expression of secretory leukoprotease inhibitor, a potent inhibitor of neutrophil elastase, was inducible in wild-type, but not in Nrf2-knockout mice. This protease/anti-protease imbalance, together with the lack of inducible expression of ARE-regulated anti-oxidant/anti-inflammatory genes, may explain the predisposition of Nrf2-knockout mice to neutrophilic inflammation. Indeed, specific activators of Nrf2 induced the expression of the SLPI gene in macrophages. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/anti-oxidant balance, but also inflammation and the protease/anti-protease balance.
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- 2005
18. Suppression of eosinophilic airway inflammation by treatment with α-galactosylceramide
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Kazuko Shibuya, Kiyohisa Sekizawa, Masaru Taniguchi, Yuko Morishima, Yukio Ishii, Toru Kimura, Akira Shibuya, Tohru Sakamoto, Takumi Kiwamoto, Takashi Iizuka, Akihiro Nomura, Yosuke Matsuno, and Ahmed E. Hegab
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medicine.diagnostic_test ,biology ,business.industry ,Immunology ,chemical and pharmacologic phenomena ,Inflammation ,respiratory system ,Eosinophil ,Natural killer T cell ,Immunoglobulin E ,chemistry.chemical_compound ,Ovalbumin ,Bronchoalveolar lavage ,medicine.anatomical_structure ,chemistry ,Eosinophilic ,medicine ,biology.protein ,Immunology and Allergy ,lipids (amino acids, peptides, and proteins) ,VCAM-1 ,medicine.symptom ,business - Abstract
To clarify the essential role of NKT cells in allergy, we investigated the contribution of NKT cells to the pathogenesis of eosinophilic airway inflammation using α-galactosylceramide (α-GalCer), a selective ligand for NKT cells. Although continuous administration of α-GalCer during ovalbumin (OVA) sensitization increased OVA-specific IgE levels and worsened eosinophil inflammation, a single administration of α-GalCer at the time of OVA challenge completely prevented eosinophilic infiltration in wild-type mice. This inhibitory effect of α-GalCer was associated with a decrease in airway hyperresponsiveness, an increase in IFN-γ, and decreases in IL-4, IL-5 and IL-13 levels in the bronchoalveolar lavage fluids. Analysis of lung lymphocytes revealed that production of IFN-γ increased in NK cells, but not in T or NKT cells, following α-GalCer administration. Induction of vascular cell adhesion molecule-1 in the lungs of wild-type mice was also significantly attenuated by treatment with α-GalCer. These effects of α-GalCer were abrogated in Jα281–/– mice, which lack NKT cells, and in wild-type mice treated with anti-IFN-γ Ab. Hence, our data indicate that α-GalCer suppresses allergen-induced eosinophilic airway inflammation, possibly by inducing a Th1 bias that results in inhibition of eosinophil adhesion to the lung vessels. See accompanying commentary: http://dx.doi.org/10.1002/eji.200535425
- Published
- 2005
19. Reply
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Michael Tiemeyer, Takumi Kiwamoto, Zhou Zhu, Bruce S. Bochner, and Toshihiko Katoh
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Text mining ,Information retrieval ,business.industry ,Immunology ,Immunology and Allergy ,Medicine ,business - Published
- 2015
20. A case of familial pulmonary mycobacterium avium complex disease
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Shigeo Otsuka, Naoto Keicho, Takefumi Saito, Yukiko Miura, Ataru Moriya, Minako Hijikata, Nariaki Kokuho, Masashi Matsuyama, Kei Shimizu, Kenji Hayashihara, and Takumi Kiwamoto
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Adult ,Male ,Cystic Fibrosis Transmembrane Conductance Regulator ,Human leukocyte antigen ,Disease ,Cftr gene ,Antigen ,Japan ,Risk Factors ,Diabetes mellitus ,Genotype ,Internal Medicine ,Medicine ,Humans ,Mycobacterium avium complex ,Genetic Predisposition to Disease ,Cation Transport Proteins ,Aged ,Mycobacterium avium-intracellulare Infection ,biology ,HLA-A Antigens ,business.industry ,General Medicine ,Middle Aged ,biology.organism_classification ,medicine.disease ,Pedigree ,Menopause ,Immunology ,Female ,business - Abstract
We report one Japanese familial line in which there were three pulmonary MAC patients and one suspected patient over two generations, most of whom were diagnosed with the nodular/bronchiectatic type. In all patients, life circumstances and bacterial strains differed at the time of diagnosis. This suggests that the genes thought to affect patient susceptibility to pulmonary MAC disease may be involved in this family line. Comprehensive genotypic analysis of the CFTR gene, HLA typing, and analysis of the NRAMP1 polymorphisms were performed in seven members of this family. The results suggest that female sex and menopause might be associated with onset of pulmonary MAC of the nodular/bronchiectatic type, and HLA-A26 antigen and diabetes mellitus might be involved in disease exacerbations.
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- 2010
21. Endogenous airway mucins carry glycans that bind Siglec-F and induce eosinophil apoptosis
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Zhou Zhu, Christopher M. Evans, Toshihiko Katoh, Michael Tiemeyer, Takumi Kiwamoto, William J. Janssen, Bruce S. Bochner, Sherry A. Hudson, and Mary Brummet
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Proteomics ,Glycan ,Immunology ,Antigens, Differentiation, Myelomonocytic ,Apoptosis ,Mice, Transgenic ,Plasma protein binding ,Ligands ,Article ,Immunophenotyping ,Mice ,chemistry.chemical_compound ,Polysaccharides ,Animals ,Immunology and Allergy ,Sialic Acid Binding Immunoglobulin-like Lectins ,Lung ,chemistry.chemical_classification ,Mucin-4 ,biology ,Mucin ,Mucins ,SIGLEC ,Lectin ,Epithelial Cells ,respiratory system ,Mucin-5B ,Molecular biology ,Sialic acid ,Eosinophils ,Phenotype ,chemistry ,Biochemistry ,biology.protein ,Cytokines ,Carrier Proteins ,Glycoprotein ,Protein Binding - Abstract
Background Sialic acid–binding, immunoglobulin-like lectin (Siglec) F is a glycan-binding protein selectively expressed on mouse eosinophils. Its engagement induces apoptosis, suggesting a pathway for ameliorating eosinophilia in the setting of asthma and other eosinophil-associated diseases. Siglec-F recognizes sialylated sulfated glycans in glycan-binding assays, but the identities of endogenous sialoside ligands and their glycoprotein carriers in vivo are unknown. Objectives To use mouse lung-derived materials to isolate, biochemically identify, and biologically characterize naturally occurring endogenous glycan ligands for Siglec-F. Methods Lungs from normal and mucin-deficient mice, as well as mouse tracheal epithelial cells, were investigated in vitro and in vivo for the expression of Siglec-F ligands. Western blotting and cytochemistry used Siglec-F-Fc as a probe for directed purification, followed by liquid chromatography–tandem mass spectrometry of recognized glycoproteins. Purified components were tested in mouse eosinophil-binding assays and flow cytometry–based cell death assays. Results We detected mouse lung glycoproteins that bound to Siglec-F; binding was sialic acid dependent. Proteomic analysis of Siglec-F binding material identified Muc5b and Muc4. Cross-affinity enrichment and histochemical analysis of lungs from mucin-deficient mice assigned and validated the identity of Muc5b as one glycoprotein ligand for Siglec-F. Purified mucin preparations carried sialylated and sulfated glycans, bound to eosinophils and induced their death in vitro . Mice conditionally deficient in Muc5b displayed exaggerated eosinophilic inflammation in response to intratracheal installation of IL-13. Conclusions These data identify a previously unrecognized endogenous anti-inflammatory property of airway mucins by which their glycans can control lung eosinophilia through engagement of Siglec-F.
- Published
- 2015
22. Association of phosphodiesterase 4D gene polymorphisms with chronic obstructive pulmonary disease: Relationship to interleukin 13 gene polymorphism
- Author
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Khalid M. Hassanein, Takumi Kiwamoto, Yosuke Matsuno, Shinsuke Homma, Yukio Ishii, Yuko Morishima, Akihiro Nomura, Wataru Saitoh, Hosny M. Massoud, Tohru Sakamoto, Takashi Iizuka, Ahmed E. Hegab, Kiyohisa Sekizawa, and Hosam H. Massoud
- Subjects
Male ,dbSNP ,Down-Regulation ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Pulmonary Disease, Chronic Obstructive ,Asian People ,Gene Frequency ,Japan ,Cyclic AMP ,Genetics ,Humans ,Genetic Predisposition to Disease ,Allele frequency ,Aged ,Interleukin-13 ,Haplotype ,Phosphodiesterase ,Interleukin ,General Medicine ,Cyclic Nucleotide Phosphodiesterases, Type 3 ,Arabs ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,respiratory tract diseases ,PDE4D Gene ,Haplotypes ,3',5'-Cyclic-AMP Phosphodiesterases ,Interleukin 13 ,Immunology ,Egypt ,Female ,Gene polymorphism - Abstract
Activation of the cyclic AMP (cAMP) signaling pathway leads to the suppression of inflammation in the airways and relaxation of airway smooth muscle. Intracellular cAMP levels are determined by a balance between the activities of adenylate cyclase and phosphodiesterases. We hypothesized that polymorphisms of the phosphodiesterase 4D (PDE4D) gene activate its protein function which leads to the downregulation of cAMP, resulting in the development of chronic obstructive pulmonary disease (COPD). A case-control study was performed using Japanese (96 COPD patients and 61 controls) and Egyptians (106 COPD patients and 72 controls) to investigate the association between the polymorphisms of the PDE4D gene and the development of COPD. Genotyping of all subjects for SNP7 (dbSNP ID, rs10075508), SNP13 (rs829259) and SNP15 (rs702531) in exon 15 of the PDE4D gene was conducted. Furthermore, the distributions of haplotypes consisting of PDE4D polymorphisms and those of interleukin (IL) 4, IL13 and beta2 adrenoceptor were analyzed. The distribution of SNP13 allele frequencies of the PDE4D gene was significantly different between the COPD and control groups in the Japanese population (p = 0.041). In haplotype analysis, haplotypes composed of PDE4D SNP7 and IL13 +2044 G/A in the Japanese population showed significant difference between the patients and controls (pcorr = 0.00048). Thus, SNP13 and haplotypes, SNP7 G/A and IL13 +2044 G/A, may be useful for predicting COPD susceptibility.
- Published
- 2006
23. Transcription factors T-bet and GATA-3 regulate development of airway remodeling
- Author
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Yukio Ishii, Shinsuke Homma, Kiyohisa Sekizawa, Yuko Morishima, Satoru Takahashi, Keigyou Yoh, Ahmed E. Hegab, Takumi Kiwamoto, Akihiro Nomura, Kazusa Ishizaki, Atsuko Maeda, Takashi Iizuka, Yosuke Matsuno, and Tohru Sakamoto
- Subjects
Pulmonary and Respiratory Medicine ,Chemokine CCL11 ,medicine.medical_treatment ,Immunoglobulins ,Mice, Transgenic ,GATA3 Transcription Factor ,Critical Care and Intensive Care Medicine ,Pathogenesis ,Interferon-gamma ,Mice ,Th2 Cells ,Fibrosis ,Transforming Growth Factor beta ,Intensive care ,medicine ,Animals ,Transcription factor ,Lung ,Hyperplasia ,business.industry ,Mucins ,Muscle, Smooth ,Hypertrophy ,respiratory system ,Th1 Cells ,medicine.disease ,Mucus ,Asthma ,respiratory tract diseases ,Eosinophils ,Disease Models, Animal ,Cytokine ,Chemokines, CC ,Immunology ,Goblet Cells ,Interleukin-4 ,business ,Airway ,T-Box Domain Proteins ,Transcription Factors - Abstract
Airway remodeling is an important feature of chronic asthma that causes irreversible airflow obstruction. Although asthma is considered to be a Th2 disease, the role of T-bet and GATA-3, the key transcription factors for differentiation toward Th1 and Th2 cells, in the pathogenesis of airway remodeling is poorly understood.We therefore examined the effects of GATA-3 or T-bet induction of Th1/Th2 bias on the development of airway remodeling in mice.The development of airway remodeling after repeated allergen challenges was analyzed using transgenic mice overexpressing either GATA-3 or T-bet.The degrees of subepithelial fibrosis and airway smooth muscle hyperplasia after repeated allergen exposure were significantly enhanced in mice overexpressing GATA-3, compared with wild-type mice. Allergen-induced goblet cell hyperplasia and mucus hypersecretion were significantly lower in mice overexpressing T-bet than in wild-type mice. Eosinophilic airway inflammation increased in mice overexpressing GATA-3, but decreased in mice overexpressing T-bet after repeated allergen exposure. Cytokine analysis revealed that the Th1/Th2 cytokine balance shifted to Th2 in lung homogenates and lung T cells of mice overexpressing GATA-3, whereas this balance shifted to Th1 in those of mice overexpressing T-bet after allergen exposure. Lung transforming growth factor-beta and eotaxin levels were associated with the degree of subepithelial fibrosis and eosinophilic airway inflammation, respectively.Overall, the results indicate that development of airway remodeling is regulated by the lung Th1/Th2 bias induced by GATA-3 and T-bet.
- Published
- 2006
24. Effect of inhaled steroids on increased collagen synthesis in asthma
- Author
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Yuko Morishima, Akihiro Nomura, Takumi Kiwamoto, Tohru Sakamoto, Sachiko Kai, Takashi Iizuka, Kiyohisa Sekizawa, and Yukio Ishii
- Subjects
Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,medicine.drug_class ,Enzyme-Linked Immunosorbent Assay ,Gastroenterology ,Severity of Illness Index ,Fluticasone propionate ,Leukocyte Count ,Pulmonary Disease, Chronic Obstructive ,fluids and secretions ,Internal medicine ,Forced Expiratory Volume ,Administration, Inhalation ,Medicine ,Humans ,Glucocorticoids ,Asthma ,Aged ,Inhalation ,business.industry ,Respiratory disease ,Sputum ,Eosinophil ,Middle Aged ,Transforming Growth Factor alpha ,medicine.disease ,Prognosis ,Immunohistochemistry ,Peptide Fragments ,respiratory tract diseases ,Eosinophils ,Procollagen peptidase ,medicine.anatomical_structure ,Immunology ,Corticosteroid ,Female ,medicine.symptom ,business ,Biomarkers ,Procollagen ,medicine.drug - Abstract
Background: We previously reported that sputum levels of procollagen type I C-terminal peptide (PICP), a marker of ongoing collagen type I deposition, are increased in proportion to airway inflammation in asthma patients. Objectives: In this study, we examined the effect of inhaled corticosteroids on increased collagen synthesis in step 2–4 asthmatics. Methods: We compared the sputum PICP concentrations of 25 steroid-naive asthmatics, 25 normal volunteers, and 10 subjects with chronic obstructive pulmonary disease. Asthma subjects were also instructed to start fluticasone propionate treatment, and the percentage of forced expiratory volume in 1 s, sputum eosinophil counts, sputum PICP concentrations, and sputum transforming growth factor-β-positive cell counts before treatment were compared with those 1 month after treatment. Results: Sputum PICP concentrations were detected in the following order: asthma group ≧ chronic obstructive pulmonary disease group > control group. Asthma patients showing high sputum PICP belonged to step 4, although there was no correlation between sputum PICP and asthma severity. Treatment with fluticasone propionate not only significantly improved the mean percentage of forced expiratory volume in 1 s (from 66.7 to 87.2%), but also decreased the mean sputum eosinophil counts (from 13.4 to 5.8%), the mean sputum PICP concentrations (from 30.8 to 10.2 ng/ml), and the mean sputum tumor growth factor-β-positive cells (from 11.3 to 2.8%). Nevertheless, a significant difference in sputum PICP concentrations was still observed between the control group and the steroid-treated asthma group. Conclusions: The present results suggest that inhaled corticosteroid treatment might reduce sputum indexes of collagen metabolism and eosinophilic inflammation in asthma patients.
- Published
- 2005
25. Role of 15-deoxy delta(12,14) prostaglandin J2 and Nrf2 pathways in protection against acute lung injury
- Author
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Takumi Kiwamoto, Koji Uchida, Tohru Sakamoto, Mie Mochizuki, Akihiro Nomura, Toru Kimura, Yuko Morishima, Yukio Ishii, Ahamed E. Hegab, Masayuki Yamamoto, Yosuke Matsuno, Ken Itoh, Kiyohisa Sekizawa, and Takashi Iizuka
- Subjects
Pulmonary and Respiratory Medicine ,NF-E2-Related Factor 2 ,Prostaglandin ,Inflammation ,Lung injury ,Pharmacology ,Critical Care and Intensive Care Medicine ,Carrageenan ,chemistry.chemical_compound ,Mice ,Intensive care ,Parenchyma ,Medicine ,Animals ,Cyclooxygenase Inhibitors ,Nitrobenzenes ,Mice, Inbred BALB C ,Respiratory Distress Syndrome ,Sulfonamides ,medicine.diagnostic_test ,Cyclooxygenase 2 Inhibitors ,business.industry ,Prostaglandin D2 ,Macrophages ,Pneumonia ,respiratory system ,respiratory tract diseases ,DNA-Binding Proteins ,Disease Models, Animal ,Bronchoalveolar lavage ,Eicosanoid ,chemistry ,Cyclooxygenase 2 ,Prostaglandin-Endoperoxide Synthases ,Immunology ,Trans-Activators ,medicine.symptom ,business - Abstract
Acute lung injury (ALI) is a disease process that is characterized by diffuse inflammation in the lung parenchyma. Recent studies demonstrated that cyclooxygenase-2 (COX-2) induced at the late phase of inflammation aids in the resolution of inflammation by generating 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2). Transcription factor Nrf2 is activated by electrophiles and exerts antiinflammatory effects by inducing the gene expression of antioxidant and detoxification enzymes.Because 15d-PGJ2 is an endogenous electrophile, we hypothesized that it protects against ALI by activating Nrf2.To test this hypothesis, we generated a reversible ALI model by intratracheal injection of carrageenin, an inducer of acute inflammation, whose stimulation has been known to induce COX-2.We found that ALI induced by carrageenin was markedly exacerbated in Nrf2-knockout mice, compared with wild-type mice. Analysis of bronchoalveolar lavage fluids also revealed that the magnitude and the duration of acute inflammation, indicated by albumin concentration and the number of neutrophils, were significantly enhanced in Nrf2-knockout mice. Treatment of wild-type mice with NS-398, a selective COX-2 inhibitor, significantly exacerbated ALI to the level of Nrf2-knockout mice. In the lungs of NS-398-treated wild-type mice, both the accumulation of 15d-PGJ2 and the induction of Nrf2 target antioxidant genes were significantly attenuated. Exogenous administration of 15d-PGJ2 reversed the exacerbating effects of NS-398 with the induction of antioxidant genes.These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.
- Published
- 2005
26. Polymorphisms of TNFalpha, IL1beta, and IL1RN genes in chronic obstructive pulmonary disease
- Author
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Kiyohisa Sekizawa, Takashi Iizuka, Yosuke Matsuno, Akihiro Nomura, Yuko Morishima, Ahmed E. Hegab, Yukio Ishii, Hosam H. Massoud, Hosny M. Massoud, Tohru Sakamoto, Wataru Saitoh, Khalid M. Hassanein, and Takumi Kiwamoto
- Subjects
Male ,Sialoglycoproteins ,Population ,Biophysics ,Biology ,Biochemistry ,Linkage Disequilibrium ,Pathogenesis ,Pulmonary Disease, Chronic Obstructive ,Japan ,Genotype ,medicine ,Humans ,education ,Molecular Biology ,Allele frequency ,Aged ,COPD ,education.field_of_study ,Polymorphism, Genetic ,Tumor Necrosis Factor-alpha ,Haplotype ,Cell Biology ,Middle Aged ,medicine.disease ,respiratory tract diseases ,Interleukin 1 Receptor Antagonist Protein ,Interleukin 1 receptor antagonist ,Haplotypes ,Immunology ,Egypt ,Female ,Gene polymorphism ,Polymorphism, Restriction Fragment Length ,Interleukin-1 - Abstract
It is recognized that genetic factors play a role in the susceptibility to COPD. COPD is characterized by airflow limitation. Chronic inflammation causes small airway disease and parenchymal destruction, leading to the airflow limitation. Polymorphisms in pro-inflammatory cytokine genes may confer a risk for the development of COPD. A case-control association study was performed in Japanese population (88 COPD patients and 61 controls) and Egyptian population (106 patients and 72 controls). Genotype and allele frequencies of the TNFalpha -308 G/A and +489 G/A polymorphisms, the IL1beta -511 C/T, -31 T/C, and +3954 C/T polymorphisms, and a VNTR polymorphism in intron 2 of the IL1RN gene were investigated. In addition, pairwise haplotype frequencies were analyzed. When studied independently, none of the polymorphisms were associated with the development of COPD in both populations. However, in the Egyptian population, the distributions of the haplotype (IL1beta -31 T/C : IL1beta +3954 C/T) were significantly different between the COPD patients and the controls (p(corr)=0.0037). Our findings suggest that this haplotype within the IL1beta gene may be involved in the pathogenesis of COPD and that the genetic factors of COPD susceptibility might be different between different populations.
- Published
- 2005
27. Association analysis of tissue inhibitor of metalloproteinase2 gene polymorphisms with COPD in Egyptians
- Author
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Yukio Ishii, Akihiro Nomura, Tohru Sakamoto, Toru Kimura, Yuko Morishima, Hosam H. Massoud, Wataru Saitoh, Hosny M. Massoud, Takumi Kiwamoto, Takashi Iizuka, Kiyohisa Sekizawa, Yoshiyuki Uchida, Ahmed E. Hegab, Mie Mochizuki, and Khalid M. Hassanein
- Subjects
Pulmonary and Respiratory Medicine ,Male ,TIMP2 ,Genotype ,Population ,Pathogenesis ,Pulmonary Disease, Chronic Obstructive ,Gene Frequency ,medicine ,COPD ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,Egyptian ,education ,Gene ,Allele frequency ,Genetic association ,Genetics ,education.field_of_study ,Tissue Inhibitor of Metalloproteinase-2 ,Polymorphism, Genetic ,business.industry ,Middle Aged ,medicine.disease ,Genotype frequency ,Case-Control Studies ,Immunology ,business - Abstract
Proteinase/antiproteinase imbalance is recognized to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). A relative increase in the activities of matrix metalloproteinases might be caused by mutations of tissue inhibitor of metalloproteinase2 (TIMP2). Recently, two polymorphisms of the TIMP2 gene, +853 G/A and −418 G/C (+551 and −720 from the translation initiation site), have been shown to be associated with the development of COPD in the Japanese population. In this study, a case-control association analysis for these polymorphisms was conducted in the Egyptian population using 106 COPD patients and 72 healthy controls. The genotype frequency of +853 G/A was significantly different between the patient and the control groups ( P =0.029), although no significant difference was detected in the allele frequency between the two groups. These results suggest that the +853 G/A polymorphism of the TIMP2 gene might be associated with COPD across ethnicities. In contrast, neither the distributions of genotype nor allele frequencies of –418 G/C were significantly different between the two groups, raising the possibility that a combination of different genetic factors contributes to the development of COPD in different ethnic groups.
- Published
- 2005
28. The Airway Mucins Muc5b and Muc4 Are Endogenous Ligands For Siglec-F and Induce Mouse Eosinophil Death
- Author
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Bruce S. Bochner, Toshihiko Katoh, Sherry A. Hudson, Christopher M. Evans, Zhou Zhu, Michael Tiemeyer, Takumi Kiwamoto, and Mary Brummet
- Subjects
Eosinophil cationic protein ,Chemistry ,Immunology ,Mucin ,Immunology and Allergy ,SIGLEC ,Endogeny ,Mouse Eosinophil ,Airway - Published
- 2014
29. Mice deficient in the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation
- Author
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Ronald L. Schnaar, Mary G. Motari, Mary Brummet, Zhou Zhu, Fan Wu, David F. Smith, Bruce S. Bochner, and Takumi Kiwamoto
- Subjects
beta-Galactoside alpha-2,3-Sialyltransferase ,Ovalbumin ,Sialyltransferase ,Immunology ,Antigens, Differentiation, Myelomonocytic ,Apoptosis ,Inflammation ,Article ,Mice ,medicine ,Animals ,Immunology and Allergy ,Lung ,Sensitization ,Mice, Knockout ,Sialic Acid Binding Immunoglobulin-like Lectins ,medicine.diagnostic_test ,biology ,Pneumonia ,respiratory system ,Eosinophil ,Sialyltransferases ,respiratory tract diseases ,Eosinophils ,Mice, Inbred C57BL ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Immunoglobulin G ,ST3GAL3 ,biology.protein ,Major basic protein ,Cytokines ,Immunization ,medicine.symptom ,Bronchoalveolar Lavage Fluid - Abstract
Background Sialic acid–binding immunoglobulin-like lectin (Siglec)-F is a proapoptotic receptor on mouse eosinophils, but little is known about its natural tissue ligand. Objective We previously reported that the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) is required for constitutive Siglec-F lung ligand synthesis. We therefore hypothesized that attenuation of ST3Gal-III will decrease Siglec-F ligand levels and enhance allergic eosinophilic airway inflammation. Methods C57BL/6 wild-type mice and St3gal3 heterozygous or homozygous deficient ( St3gal3 +/− and St3gal3 −/− ) mice were used. Eosinophilic airway inflammation was induced through sensitization to ovalbumin (OVA) and repeated airway OVA challenge. Siglec-F human IgG 1 fusion protein (Siglec-F-Fc) was used to detect Siglec-F ligands. Lung tissue and bronchoalveolar lavage fluid (BALF) were analyzed for inflammation, as well as various cytokines and chemokines. Serum was analyzed for allergen-specific immunoglobulin levels. Results Western blotting with Siglec-F-Fc detected approximately 500-kDa and approximately 200-kDa candidate Siglec-F ligands that were less abundant in St3gal3 +/− lung extracts and nearly absent in St3gal3 −/− lung extracts. After OVA sensitization and challenge, Siglec-F ligands were increased in wild-type mouse lungs but less so in St3gal3 mutants, whereas peribronchial and BALF eosinophil numbers were greater in the mutants, with the following rank order: St3gal3 −/− ≥ St3gal3 +/− > wild-type mice. Levels of various cytokines and chemokines in BALF were not significantly different among these 3 types of mice, although OVA-specific serum IgG 1 levels were increased in St3gal3 −/− mice. Conclusions After OVA sensitization and challenge, St3gal3 +/− and St3gal3 −/− mice have more intense allergic eosinophilic airway inflammation and less sialylated Siglec-F ligands in their airways. One possible explanation for these findings is that levels of sialylated airway ligands for Siglec-F might be diminished in mice with attenuated levels of ST3Gal-III, resulting in a reduction in a natural proapoptotic pathway for controlling airway eosinophilia.
- Published
- 2014
30. Mice with Attenuated Expression of the α2,3 Sialyltransferase ST3gal-III (St3gal3) Display Enhanced Allergic Eosinophilic Airway Inflammation
- Author
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Ronald L. Schnaar, Mary Brummet, Mary G. Motari, Takumi Kiwamoto, Bruce S. Bochner, and Zhou Zhu
- Subjects
Pathology ,medicine.medical_specialty ,biology ,business.industry ,Sialyltransferase ,Immunology ,Airway inflammation ,ST3Gal III ,ST3GAL3 ,Eosinophilic ,biology.protein ,Immunology and Allergy ,Medicine ,business - Published
- 2013
31. Similarities And Differences Between Lung Ligands For Mouse Siglec-f And Human Siglec-8
- Author
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H.J. Na, David F. Smith, Takumi Kiwamoto, Bruce S. Bochner, and Mary Brummet
- Subjects
Lung ,medicine.anatomical_structure ,Chemistry ,Immunology ,medicine ,Immunology and Allergy ,SIGLEC - Published
- 2012
32. MMP14 gene polymorphisms in chronic obstructive pulmonary disease
- Author
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Yuko Morishima, Hosam H. Massoud, Takashi Iizuka, Takumi Kiwamoto, Yukio Ishii, Tohru Sakamoto, Sachiko Kai, Khalid M. Hassanein, Hosny M. Massoud, Kiyohisa Sekizawa, Ahmed E. Hegab, Akihiro Nomura, Wataru Saitoh, and Yosuke Matsuno
- Subjects
Male ,Linkage disequilibrium ,Genotype ,Matrix Metalloproteinases, Membrane-Associated ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Pathogenesis ,Pulmonary Disease, Chronic Obstructive ,Exon ,Gene Frequency ,Japan ,Genetics ,medicine ,Humans ,Promoter Regions, Genetic ,Alleles ,Aged ,COPD ,Haplotype ,General Medicine ,medicine.disease ,Matrix Metalloproteinases ,Respiratory Function Tests ,respiratory tract diseases ,Genotype frequency ,Haplotypes ,Immunology ,MMP14 ,Egypt ,Female - Abstract
Proteinase/antiproteinase imbalance is a widely accepted theory for the pathogenesis of COPD. Among various proteinases, matrix metalloproteinases (MMPs) digest extracellular matrix of the lung and play significant roles in the development of COPD. Polymorphisms of an MMP that upregulate its activity may result in the degradation of the lung matrix. A case-control study was performed to investigate the association of polymorphisms of the MMP14 gene with COPD. Japanese subjects (96 COPD patients and 61 controls) and Egyptian subjects (106 COPD patients and 72 controls) were recruited. Each subject was genotyped for seven single nucleotide polymorphisms (SNPs) of the MMP14 gene; -165 G/T and -72 G/A in the promoter region, +221 C/T in exon 1, +6727 C/G and +6767 G/A in exon 5, +7096 T/C in exon 6, and +8153 G/A in exon 8. The distributions of the genotype frequencies of these SNPs were not significantly different between the COPD patients and the controls in either ethnic group after correction of multiple comparisons. In the haplotype analysis, however, the haplotype -165 T : +221 T : +6727 C : +7096 C had a significantly higher frequency in the Egyptian COPD group than the control group (pcorr = 0.0063). The haplotype of the MMP14 gene, -165 T : +221 T : +6727 C : +7096 C, might be involved in the pathogenesis of COPD.
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