The Experts below are selected from a list of 333 Experts worldwide ranked by ideXlab platform
Shioko Kimura - One of the best experts on this subject based on the ideXlab platform.
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a novel pathway of lps uptake through syndecan 1 leading to pyroptotic cell death
eLife, 2018Co-Authors: Shigetoshi Yokoyama, Yan Cai, Mitsuhiro Yoneda, Takeshi Tomita, Miyuki Murata, Aprile L Pilon, Raul E Cachau, Shioko KimuraAbstract:Intracellular lipopolysaccharide (LPS) triggers the non-canonical inflammasome pathway, resulting in pyroptosis of innate immune cells. In addition to its well-known proinflammatory role, LPS can directly cause regression of some tumors, although the underlying mechanism has remained unknown. Here we show that Secretoglobin(SCGB)3A2, a small protein predominantly secreted in airways, chaperones LPS to the cytosol through the cell surface receptor syndecan-1; this leads to pyroptotic cell death driven by caspase-11. SCGB3A2 and LPS co-treatment significantly induced pyroptosis of macrophage RAW264.7 cells and decreased cancer cell proliferation in vitro, while SCGB3A2 treatment resulted in reduced progression of xenograft tumors in mice. These data suggest a conserved function for SCGB3A2 in the innate immune system and cancer cells. These findings demonstrate a critical role for SCGB3A2 as an LPS delivery vehicle; they reveal one mechanism whereby LPS enters innate immune cells leading to pyroptosis, and they clarify the direct effect of LPS on cancer cells.
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co expression of achaete scute homologue 1 and calcitonin gene related peptide during nnk induced pulmonary neuroendocrine hyperplasia and carcinogenesis in hamsters
Journal of Cancer, 2016Co-Authors: Xu Naizhen, Ilona R Linnoila, Shioko KimuraAbstract:Achaete-scute homologue-1 or ASCL1 (MASH1, hASH1) plays roles in neural development and pulmonary neuroendocrine (NE) differentiation, and it is expressed in certain lung cancers. This study was aimed to assess whether and/or how ASCL1 plays a role in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced pulmonary NE hyperplasia and carcinogenesis in hamsters. Hamsters were injected 3 times weekly with either NNK or solvent alone (control) for treatment periods of 6 and 24 weeks, both without and with 6-week recovery. Immunohistochemical analysis was carried out to examine the expressions of ASCL1, CGRP (calcitonin gene-related peptide), Secretoglobin SCGB1A1 (club [Clara] cell specific 10 kD protein, CC10, CCSP), synaptophysin (SYP), and PCNA (proliferating cell nuclear antigen). The number of ASCL1-expressing NE foci per airway increased from 0.8 in controls to 1.6 and 2.0 during NNK exposure for 6 and 24 weeks, respectively, and the number of cells per foci doubled after NNK exposure. Most ASCL1-expressing cells in NEBs (neuroepithelial bodies) were also CGRP immunoreactive; NNK enhanced this co-expression with CGRP, a NE marker with known proliferation-promoting properties. NNK also increased PCNA expression within NE foci. NNK-induced tumors showed no immunoreactivity for NE markers. This study confirms ASCL1 as an excellent marker for pulmonary NE cells and demonstrates CGRP co-expression in ASCL1-positive NEB cells participating in NNK-induced NE hyperplasia.
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RESEARCH ARTICLE Open Access Transgenically-expressed Secretoglobin 3A2
2016Co-Authors: Yan Cai, Arjun Guha, Mitsuhiro Yoneda, Reiko Kurotani, Hiroyuki Abe, Takeshi Tomita, Minoru Okamoto, Taketomo Kido, Wayne Mitzner, Shioko KimuraAbstract:Background: Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, is predominantly expressed in airway epithelial cells. While SCGB3A2 is known to have anti-inflammatory, growth factor, and anti-fibrotic activities, whether SCGB3A2 has any other roles, particularly in lung homeostasis and disease has not been demonstrated in vivo. The aim of this study was to address these questions in mice. Methods: A transgenic mouse line that expresses SCGB3A2 in the lung using the human surfactant protein-C promoter was established. Detailed histological, immunohistochemical, physiological, and molecular characterization of the Scgb3a2-transgenic mouse lungs were carried out. Scgb3a2-transgenic and wild-type mice were subjected to bleomycin-induced pulmonary fibrosis model, and their lungs and bronchoalveolar lavage fluids were collected at various time points during 9 weeks post-bleomycin treatment for further analysis. Results: Adult Scgb3a2-transgenic mouse lungs expressed approximately five-fold higher levels of SCGB3A2 protein in comparison to wild-type mice as determined by western blotting of lung tissues. Immunohistochemistry showed that expression was localized to alveolar type II cells in addition to airway epithelial cells, thus accurately reflecting the site of surfactant protein-C expression. Scgb3a2-transgenic mice showed normal lung development and histology, and no overt gross phenotypes. However, when subjected to a bleomycin-induced pulmonary fibrosis model, they initiall
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Research Article Secretoglobin Superfamily Protein SCGB3A2 Deficiency Potentiates Ovalbumin-Induced Allergic Pulmonary Inflammation
2016Co-Authors: Taketomo Kido, Yan Cai, Mitsuhiro Yoneda, Tsutomu Matsubara, Jerrold M. Ward, Shioko KimuraAbstract:Copyright © 2014 Taketomo Kido et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of smallmolecular weight, whichmay play a role in lung inflammation, is predominantly expressed in airway epithelial cells. In order to understand the physiological role of SCGB3A2, Scgb3a2−/ − mice were generated and characterized. Scgb3a2−/ − mice did not exhibit any overt phenotypes. In ovalbumin- (OVA-) induced airway allergy inflammation model, Scgb3a2−/ − mice in mixed background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenic Scgb3a2−/ − mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates.These results indicate that the loss of SCGB3A2 function was influenced by amodifier gene(s) in mixed genetic background and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent. 1
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SCGB3A2 Inhibits Acrolein-Induced Apoptosis through Decreased p53
2014Co-Authors: Reiko Kurotani, Reika Shima, Yuki Miyano, Satoshi Sakahara, Yoshie Matsumoto, Yoko Shibata, Hiroyuki Abe, Shioko KimuraAbstract:Chronic obstructive pulmonary disease (COPD), a major global health problem with increasing morbidity and mortality rates, is anticipated to become the third leading cause of death worldwide by 2020. COPD arises from exposure to cigarette smoke. Acrolein, which is contained in cigarette smoke, is the most important risk factor for COPD. It causes lung injury through altering apoptosis and causes inflammation by augmenting p53 phosphorylation and producing reactive oxygen species (ROS). Secretoglobin (SCGB) 3A2, a secretory protein predominantly present in the epithelial cells of the lungs and trachea, is a cytokine-like small molecule having anti-inflammatory, antifibrotic, and growth factor activities. In this study, the effect of SCGB3A2 on acrolein-related apoptosis was investigated using the mouse fibroblast cell line MLg as the first step in determining the possible therapeutic value of SCGB3A2 in COPD. Acrolein increased the production of ROS and phosphorylation of p53 and induced apoptosis in MLg cells. While the extent of ROS production induced by acrolein was not affected by SCGB3A2, p53 phosphorylation was significantly decreased by SCGB3A2. These results demonstrate that SCGB3A2 inhibited acrolein-induced apoptosis through decreased p53 phosphorylation, not altered ROS levels. Key words: Secretoglobin (SCGB) 3A2, chronic obstructive pulmonary disease (COPD), apoptosis, acrolein, p53 I
Yan Cai - One of the best experts on this subject based on the ideXlab platform.
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a novel pathway of lps uptake through syndecan 1 leading to pyroptotic cell death
eLife, 2018Co-Authors: Shigetoshi Yokoyama, Yan Cai, Mitsuhiro Yoneda, Takeshi Tomita, Miyuki Murata, Aprile L Pilon, Raul E Cachau, Shioko KimuraAbstract:Intracellular lipopolysaccharide (LPS) triggers the non-canonical inflammasome pathway, resulting in pyroptosis of innate immune cells. In addition to its well-known proinflammatory role, LPS can directly cause regression of some tumors, although the underlying mechanism has remained unknown. Here we show that Secretoglobin(SCGB)3A2, a small protein predominantly secreted in airways, chaperones LPS to the cytosol through the cell surface receptor syndecan-1; this leads to pyroptotic cell death driven by caspase-11. SCGB3A2 and LPS co-treatment significantly induced pyroptosis of macrophage RAW264.7 cells and decreased cancer cell proliferation in vitro, while SCGB3A2 treatment resulted in reduced progression of xenograft tumors in mice. These data suggest a conserved function for SCGB3A2 in the innate immune system and cancer cells. These findings demonstrate a critical role for SCGB3A2 as an LPS delivery vehicle; they reveal one mechanism whereby LPS enters innate immune cells leading to pyroptosis, and they clarify the direct effect of LPS on cancer cells.
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RESEARCH ARTICLE Open Access Transgenically-expressed Secretoglobin 3A2
2016Co-Authors: Yan Cai, Arjun Guha, Mitsuhiro Yoneda, Reiko Kurotani, Hiroyuki Abe, Takeshi Tomita, Minoru Okamoto, Taketomo Kido, Wayne Mitzner, Shioko KimuraAbstract:Background: Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, is predominantly expressed in airway epithelial cells. While SCGB3A2 is known to have anti-inflammatory, growth factor, and anti-fibrotic activities, whether SCGB3A2 has any other roles, particularly in lung homeostasis and disease has not been demonstrated in vivo. The aim of this study was to address these questions in mice. Methods: A transgenic mouse line that expresses SCGB3A2 in the lung using the human surfactant protein-C promoter was established. Detailed histological, immunohistochemical, physiological, and molecular characterization of the Scgb3a2-transgenic mouse lungs were carried out. Scgb3a2-transgenic and wild-type mice were subjected to bleomycin-induced pulmonary fibrosis model, and their lungs and bronchoalveolar lavage fluids were collected at various time points during 9 weeks post-bleomycin treatment for further analysis. Results: Adult Scgb3a2-transgenic mouse lungs expressed approximately five-fold higher levels of SCGB3A2 protein in comparison to wild-type mice as determined by western blotting of lung tissues. Immunohistochemistry showed that expression was localized to alveolar type II cells in addition to airway epithelial cells, thus accurately reflecting the site of surfactant protein-C expression. Scgb3a2-transgenic mice showed normal lung development and histology, and no overt gross phenotypes. However, when subjected to a bleomycin-induced pulmonary fibrosis model, they initiall
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Research Article Secretoglobin Superfamily Protein SCGB3A2 Deficiency Potentiates Ovalbumin-Induced Allergic Pulmonary Inflammation
2016Co-Authors: Taketomo Kido, Yan Cai, Mitsuhiro Yoneda, Tsutomu Matsubara, Jerrold M. Ward, Shioko KimuraAbstract:Copyright © 2014 Taketomo Kido et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of smallmolecular weight, whichmay play a role in lung inflammation, is predominantly expressed in airway epithelial cells. In order to understand the physiological role of SCGB3A2, Scgb3a2−/ − mice were generated and characterized. Scgb3a2−/ − mice did not exhibit any overt phenotypes. In ovalbumin- (OVA-) induced airway allergy inflammation model, Scgb3a2−/ − mice in mixed background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenic Scgb3a2−/ − mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates.These results indicate that the loss of SCGB3A2 function was influenced by amodifier gene(s) in mixed genetic background and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent. 1
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Secretoglobin Superfamily Protein SCGB3A2 Deficiency Potentiates Ovalbumin-Induced Allergic Pulmonary Inflammation
Hindawi Limited, 2013Co-Authors: Taketomo Kido, Yan Cai, Mitsuhiro Yoneda, Tsutomu Matsubara, Jerrold M. Ward, Shioko KimuraAbstract:Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, which may play a role in lung inflammation, is predominantly expressed in airway epithelial cells. In order to understand the physiological role of SCGB3A2,Scgb3a2−/−mice were generated and characterized.Scgb3a2−/−mice did not exhibit any overt phenotypes. In ovalbumin- (OVA-) induced airway allergy inflammation model,Scgb3a2−/−mice in mixed background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenicScgb3a2−/−mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates. These results indicate that the loss of SCGB3A2 function was influenced by a modifier gene(s) in mixed genetic background and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent.
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neuroepithelial body microenvironment is a niche for a distinct subset of clara like precursors in the developing airways
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Arjun Guha, Shioko Kimura, Michelle Vasconcelos, Yan Cai, Mitsuhiro Yoneda, Anne Hinds, Jun Qian, Lauren K Dickel, Jane E Johnson, Jinjin GuoAbstract:Clara cells of mammalian airways have multiple functions and are morphologically heterogeneous. Although Notch signaling is essential for the development of these cells, it is unclear how Notch influences Clara cell specification and if diversity is established among Clara cell precursors. Here we identify expression of the Secretoglobin Scgb3a2 and Notch activation as early events in a program of secretory cell fate determination in developing murine airways. We show that Scgb3a2 expression in vivo is Notch-dependent at early stages and ectopically induced by constitutive Notch1 activation, and also that in vitro Notch signaling together with the pan-airway transcription factor Ttf1 (Nkx2.1) synergistically regulate Secretoglobin gene transcription. Furthermore, we identified a subpopulation of secretory precursors juxtaposed to presumptive neuroepithelial bodies (NEBs), distinguished by their strong Scgb3a2 and uroplakin 3a (Upk3a) signals and reduced Ccsp (Scgb1a1) expression. Genetic ablation of Ascl1 prevented NEB formation and selectively interfered with the formation of this subpopulation of cells. Lineage labeling of Upk3a-expressing cells during development showed that these cells remain largely uncommitted during embryonic development and contribute to Clara and ciliated cells in the adult lung. Together, our findings suggest a role for Notch in the induction of a Clara cell-specific program of gene expression, and reveals that the NEB microenvironment in the developing airways is a niche for a distinct subset of Clara-like precursors.
Alfred Bernard - One of the best experts on this subject based on the ideXlab platform.
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update of the human Secretoglobin scgb gene superfamily and an example of evolutionary bloom of androgen binding protein genes within the mouse scgb gene superfamily
Human Genomics, 2011Co-Authors: Brian C Jackson, Alfred Bernard, David C Thompson, Mathew W Wright, Monica S Mcandrews, Daniel W Nebert, Vasilis VasiliouAbstract:The Secretoglobins (SCGBs) comprise a family of small, secreted proteins found in animals exclusively of mammalian lineage. There are 11 human SCGB genes and five pseudogenes. Interestingly, mice have 68 Scgb genes, four of which are highly orthologous to human SCGB genes; the remainder represent an 'evolutionary bloom' and make up a large gene family represented by only six counterparts in humans. SCGBs are found in high concentrations in many mammalian secretions, including fluids of the lung, lacrimal gland, salivary gland, prostate and uterus. Whereas the biological activities of most individual SCGBs have not been fully characterised, what already has been discovered suggests that this family has an important role in the modulation of inflammation, tissue repair and tumorigenesis. In mice, the large Scgb1b and Scgb2b gene families encode the androgen-binding proteins, which have been shown to play a role in mate selection. Although much has been learned about SCGBs in recent years, clearly more research remains to be done to allow a better understanding of the roles of these proteins in human health and disease. Such information is predicted to reveal valuable novel drug targets for the treatment of inflammation, as well as designing biomarkers that might identify tissue damage or cancer.
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uteroglobin related protein 1 and clara cell protein in induced sputum of patients with asthma and rhinitis
Chest, 2007Co-Authors: Claire De Burbure, Xavier Dumont, Antonio Mutti, Patrizia Pignatti, Massimo Corradi, Mario Malerba, Andre Clippe, G Moscato, Alfred BernardAbstract:Rationale: Uteroglobin-related protein 1 (UGRP1) and Clara cell protein (CC16), members of the Secretoglobin family, increasingly appear to play a role in airway inflammatory response. OBJECTIVE: To explore levels of UGRP1 and CC16 in induced sputum of patients with asthma and rhinitis. METHODS: Induced-sputum samples of patients with asthma or rhinitis (n = 32 each; atopic asthma, n = 24; atopic rhinitis, n = 20) and from 19 nonsmoking nonatopic control subjects were analyzed for cytology and levels of UGRP1, CC16, and albumin. Measurements and main results: Sputum UGRP1 increased in both asthma and rhinitis, most strikingly so in asthma, in which changes were most significant in atopic individuals. By contrast, sputum CC16 did not change significantly in either condition, although it was positively correlated with UGRP1 in patients and control subjects. Changes in sputum UGRP1 in atopic asthma were not linked to permeability changes reflected by increased albumin levels but correlated positively with sputum macrophages and negatively with eosinophils. The observed differences in UGRP1 and CC16 may be linked to different cell populations being responsible for their secretion; UGRP1 is mainly secreted in larger conducting airways, whereas CC16 is mainly secreted by the nasal and peripheral airways epithelium. CONCLUSIONS: The increase in UGRP1 but not of CC16 in asthma and rhinitis suggests that UGRP1 may play a role in these inflammatory diseases.
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exploring the time dependence of serum clara cell protein as a biomarker of pulmonary injury in humans
Chest, 2006Co-Authors: Ragnberth Helleday, Gunnar F. Nordberg, Bertil Forsberg, Ian Mudway, Alfred Bernard, Bo Segerstedt, Anders BlombergAbstract:We have previously demonstrated Clara cell protein (CC16) [Secretoglobin 1A1] in serum to be a highly sensitive biomarker of altered lung epithelial permeability after ozone challenge. As a previous experimental study has indicated a diurnal variation in serum CC16 in humans, the aims of the present investigation were to confirm this observation and to attempt to model the diurnal variation in CC16 concentrations. In 18 healthy nonsmoking subjects, peripheral blood samples were drawn at six sampling points over a 15-h period and repeated twice within 3 to 4 weeks. A clear within-day variation was revealed in serum CC16 concentrations, falling significantly from baseline levels between the 11:30 am and 10:00 pm time points (p = 0.000). Furthermore, it was shown that this within-day variation was reproducible regardless of subject or day, enabling the diurnal variation in serum CC16 to be modeled and fitted a second-degree polynomial for the observed time span. In conclusion, the present data demonstrate a pronounced time-dependent diurnal variation in serum levels of CC16, which can be mathematically compensated for, when addressing the issue of an air pollution-induced effect on CC16 in field studies.
Mitsuhiro Yoneda - One of the best experts on this subject based on the ideXlab platform.
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a novel pathway of lps uptake through syndecan 1 leading to pyroptotic cell death
eLife, 2018Co-Authors: Shigetoshi Yokoyama, Yan Cai, Mitsuhiro Yoneda, Takeshi Tomita, Miyuki Murata, Aprile L Pilon, Raul E Cachau, Shioko KimuraAbstract:Intracellular lipopolysaccharide (LPS) triggers the non-canonical inflammasome pathway, resulting in pyroptosis of innate immune cells. In addition to its well-known proinflammatory role, LPS can directly cause regression of some tumors, although the underlying mechanism has remained unknown. Here we show that Secretoglobin(SCGB)3A2, a small protein predominantly secreted in airways, chaperones LPS to the cytosol through the cell surface receptor syndecan-1; this leads to pyroptotic cell death driven by caspase-11. SCGB3A2 and LPS co-treatment significantly induced pyroptosis of macrophage RAW264.7 cells and decreased cancer cell proliferation in vitro, while SCGB3A2 treatment resulted in reduced progression of xenograft tumors in mice. These data suggest a conserved function for SCGB3A2 in the innate immune system and cancer cells. These findings demonstrate a critical role for SCGB3A2 as an LPS delivery vehicle; they reveal one mechanism whereby LPS enters innate immune cells leading to pyroptosis, and they clarify the direct effect of LPS on cancer cells.
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RESEARCH ARTICLE Open Access Transgenically-expressed Secretoglobin 3A2
2016Co-Authors: Yan Cai, Arjun Guha, Mitsuhiro Yoneda, Reiko Kurotani, Hiroyuki Abe, Takeshi Tomita, Minoru Okamoto, Taketomo Kido, Wayne Mitzner, Shioko KimuraAbstract:Background: Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, is predominantly expressed in airway epithelial cells. While SCGB3A2 is known to have anti-inflammatory, growth factor, and anti-fibrotic activities, whether SCGB3A2 has any other roles, particularly in lung homeostasis and disease has not been demonstrated in vivo. The aim of this study was to address these questions in mice. Methods: A transgenic mouse line that expresses SCGB3A2 in the lung using the human surfactant protein-C promoter was established. Detailed histological, immunohistochemical, physiological, and molecular characterization of the Scgb3a2-transgenic mouse lungs were carried out. Scgb3a2-transgenic and wild-type mice were subjected to bleomycin-induced pulmonary fibrosis model, and their lungs and bronchoalveolar lavage fluids were collected at various time points during 9 weeks post-bleomycin treatment for further analysis. Results: Adult Scgb3a2-transgenic mouse lungs expressed approximately five-fold higher levels of SCGB3A2 protein in comparison to wild-type mice as determined by western blotting of lung tissues. Immunohistochemistry showed that expression was localized to alveolar type II cells in addition to airway epithelial cells, thus accurately reflecting the site of surfactant protein-C expression. Scgb3a2-transgenic mice showed normal lung development and histology, and no overt gross phenotypes. However, when subjected to a bleomycin-induced pulmonary fibrosis model, they initiall
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Research Article Secretoglobin Superfamily Protein SCGB3A2 Deficiency Potentiates Ovalbumin-Induced Allergic Pulmonary Inflammation
2016Co-Authors: Taketomo Kido, Yan Cai, Mitsuhiro Yoneda, Tsutomu Matsubara, Jerrold M. Ward, Shioko KimuraAbstract:Copyright © 2014 Taketomo Kido et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of smallmolecular weight, whichmay play a role in lung inflammation, is predominantly expressed in airway epithelial cells. In order to understand the physiological role of SCGB3A2, Scgb3a2−/ − mice were generated and characterized. Scgb3a2−/ − mice did not exhibit any overt phenotypes. In ovalbumin- (OVA-) induced airway allergy inflammation model, Scgb3a2−/ − mice in mixed background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenic Scgb3a2−/ − mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates.These results indicate that the loss of SCGB3A2 function was influenced by amodifier gene(s) in mixed genetic background and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent. 1
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Secretoglobin Superfamily Protein SCGB3A2 Deficiency Potentiates Ovalbumin-Induced Allergic Pulmonary Inflammation
Hindawi Limited, 2013Co-Authors: Taketomo Kido, Yan Cai, Mitsuhiro Yoneda, Tsutomu Matsubara, Jerrold M. Ward, Shioko KimuraAbstract:Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, which may play a role in lung inflammation, is predominantly expressed in airway epithelial cells. In order to understand the physiological role of SCGB3A2,Scgb3a2−/−mice were generated and characterized.Scgb3a2−/−mice did not exhibit any overt phenotypes. In ovalbumin- (OVA-) induced airway allergy inflammation model,Scgb3a2−/−mice in mixed background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenicScgb3a2−/−mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates. These results indicate that the loss of SCGB3A2 function was influenced by a modifier gene(s) in mixed genetic background and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent.
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neuroepithelial body microenvironment is a niche for a distinct subset of clara like precursors in the developing airways
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Arjun Guha, Shioko Kimura, Michelle Vasconcelos, Yan Cai, Mitsuhiro Yoneda, Anne Hinds, Jun Qian, Lauren K Dickel, Jane E Johnson, Jinjin GuoAbstract:Clara cells of mammalian airways have multiple functions and are morphologically heterogeneous. Although Notch signaling is essential for the development of these cells, it is unclear how Notch influences Clara cell specification and if diversity is established among Clara cell precursors. Here we identify expression of the Secretoglobin Scgb3a2 and Notch activation as early events in a program of secretory cell fate determination in developing murine airways. We show that Scgb3a2 expression in vivo is Notch-dependent at early stages and ectopically induced by constitutive Notch1 activation, and also that in vitro Notch signaling together with the pan-airway transcription factor Ttf1 (Nkx2.1) synergistically regulate Secretoglobin gene transcription. Furthermore, we identified a subpopulation of secretory precursors juxtaposed to presumptive neuroepithelial bodies (NEBs), distinguished by their strong Scgb3a2 and uroplakin 3a (Upk3a) signals and reduced Ccsp (Scgb1a1) expression. Genetic ablation of Ascl1 prevented NEB formation and selectively interfered with the formation of this subpopulation of cells. Lineage labeling of Upk3a-expressing cells during development showed that these cells remain largely uncommitted during embryonic development and contribute to Clara and ciliated cells in the adult lung. Together, our findings suggest a role for Notch in the induction of a Clara cell-specific program of gene expression, and reveals that the NEB microenvironment in the developing airways is a niche for a distinct subset of Clara-like precursors.
Kimura Shioko - One of the best experts on this subject based on the ideXlab platform.
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Transgenically-expressed Secretoglobin 3A2 accelerates resolution of bleomycin-induced pulmonary fibrosis in mice
'Springer Science and Business Media LLC', 2015Co-Authors: Cai Yan, Kurotani Reiko, Tomita Takeshi, Guha Arjun, Yoneda Mitsuhiro, Kido Taketomo, Okamoto Minoru, Abe Hiroyuki, Mitzner Wayne, Kimura ShiokoAbstract:[Background] Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, is predominantly expressed in airway epithelial cells. While SCGB3A2 is known to have anti-inflammatory, growth factor, and anti-fibrotic activities, whether SCGB3A2 has any other roles, particularly in lung homeostasis and disease has not been demonstrated in vivo. The aim of this study was to address these questions in mice. [Methods] A transgenic mouse line that expresses SCGB3A2 in the lung using the human surfactant protein-C promoter was established. Detailed histological, immunohistochemical, physiological, and molecular characterization of the Scgb3a2-transgenic mouse lungs were carried out. Scgb3a2-transgenic and wild-type mice were subjected to bleomycin-induced pulmonary fibrosis model, and their lungs and bronchoalveolar lavage fluids were collected at various time points during 9 weeks post-bleomycin treatment for further analysis. [Results] Adult Scgb3a2-transgenic mouse lungs expressed approximately five-fold higher levels of SCGB3A2 protein in comparison to wild-type mice as determined by western blotting of lung tissues. Immunohistochemistry showed that expression was localized to alveolar type II cells in addition to airway epithelial cells, thus accurately reflecting the site of surfactant protein-C expression. Scgb3a2-transgenic mice showed normal lung development and histology, and no overt gross phenotypes. However, when subjected to a bleomycin-induced pulmonary fibrosis model, they initially exhibited exacerbated fibrosis at 3 weeks post-bleomycin administration that was more rapidly resolved by 6 weeks as compared with wild-type mice, as determined by lung histology, Masson Trichrome staining and hydroxyproline content, inflammatory cell numbers, expression of collagen genes, and proinflammatory cytokine levels. The decrease of fibrosis coincided with the increased expression of SCGB3A2 in Scgb3a2-transgenic lungs. [Conclusions] These results demonstrate that SCGB3A2 is an anti-fibrotic agent, and suggest a possible therapeutic use of recombinant SCGB3A2 in the treatment of pulmonary fibrosis
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Neuroepithelial Body Microenvironment Is a Niche for a Distinct Subset of Clara-Like Precursors in the Developing Airways
'Proceedings of the National Academy of Sciences', 2014Co-Authors: Guha Arjun, Vasconcelos Michelle, Cai Yan, Yoneda Mitsuhiro, Hinds Anne, Qian Jun, Li Guihua, Dickel Lauren, Johnson, Jane E., Kimura ShiokoAbstract:Clara cells of mammalian airways have multiple functions and are morphologically heterogeneous. Although Notch signaling is essential for the development of these cells, it is unclear how Notch influences Clara cell specification and if diversity is established among Clara cell precursors. Here we identify expression of the Secretoglobin Scgb3a2 and Notch activation as early events in a program of secretory cell fate determination in developing murine airways. We show that Scgb3a2 expression in vivo is Notch-dependent at early stages and ectopically induced by constitutive Notch1 activation, and also that in vitro Notch signaling together with the pan-airway transcription factor Ttf1 (Nkx2.1) synergistically regulate Secretoglobin gene transcription. Furthermore, we identified a subpopulation of secretory precursors juxtaposed to presumptive neuroepithelial bodies (NEBs), distinguished by their strong Scgb3a2 and uroplakin 3a (Upk3a) signals and reduced Ccsp (Scgb1a1) expression. Genetic ablation of Ascl1 prevented NEB formation and selectively interfered with the formation of this subpopulation of cells. Lineage labeling of Upk3a-expressing cells during development showed that these cells remain largely uncommitted during embryonic development and contribute to Clara and ciliated cells in the adult lung. Together, our findings suggest a role for Notch in the induction of a Clara cell-specific program of gene expression, and reveals that the NEB microenvironment in the developing airways is a niche for a distinct subset of Clara-like precursors.Molecular and Cellular Biolog
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Noninvasive Monitoring of Pulmonary Fibrosis by Targeting Matrix Metalloproteinases (MMPs)
AMER CHEMICAL SOC, 2013Co-Authors: Cai Yan, Kimura Shioko, Zhu Lei, Zhang Fan, Niu Gang, Lee Seulki, Chen XiaoyuanAbstract:Major State Basic Research Development Program of China (973 Program) [2013CB733802]; National Science Foundation of China (NSFC) [81201129, 81101101, 81201086, 81201190, 51273165]; Chinese Academy of Sciences Professorship for Senior International Scientists [2011T2J06]; Key Project of Chinese Ministry of Education [212149]; Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Cancer Institute (NCI), National Institutes of Health (NIH)While idiopathic pulmonary fibrosis (PF) is a devastating lung disease, the management of PP including effective monitoring of disease progression remains a challenge. Herein, we introduce a novel, fast, and ultrasensitive metalloproteinase (MMP) activatable optical probe, named MMP-P12, to noninvasively monitor PF progression and response to PF treatment A bleomycin (BLM)-induced mouse PF model was subjected noninvasively to optical imaging at various time points after BLM treatment The mouse PF model developed fibrosis during 21 days of experimental period, and the progression of PF was well correlated with the stepwise increase of MMP-2 expression as examined by quantitative RT-PCR and Western blot analysis on the 7-, 14-, and 21 day post-BLM administration. On these days, MMP-activated fluorescence images were acquired in vivo and ex vivo. Signal quantification showed time dependent lung specific incremental increases in fluorescence signals. As a treatment for PF, Secretoglobin 3A2 was daily administered intravenously for five days starting on day seven of BLM administration, which resulted in reduced MMP-2 activity and reduction of PF as previously demonstrated Importantly, the fluorescence signal that reflected MMP activity also decreased in intensity. In conclusion, MMPs may play an important role in PF development and the, MMP-P12 probe, could be a promising tool for PP detection, even at an early stage of the disease as well as an indicator of therapy response
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Expression of Secretoglobin3A2 (SCGB3A2) in primary pulmonary carcinomas
福島医学会, 2008Co-Authors: Tachihara-yoshikawa Motoko, Kimura Shioko, Ishida Takashi, Watanabe Kana, Sugawara Aya, Kanazawa Kenya, Kanno Ryuzo, Suzuki Toshimitsu, Niimi Tomoaki, Munakata MitsuruAbstract:Secretoglobin (SCGB) 3A2 is a downstream target gene for the thyroid transcription factor-1 (TITF1). SCGB3A2 plays a role as an anti-inflammatory agent, however, its role in primary pulmonary carcinomas has not been examined. We assessed immunohistochemical expression of SCGB3A2 in primary pulmonary carcinomas and evaluated the correlation between the expression and histopathological phenotypes and prognosis. One hundred and fifty-six primary lung cancers undergone for surgical resection were examined. The percentages of SCGB3A2 positive cells were scored and tumors had immunoreactivity in more than 10% of tumor cells were considered positive for SCGB3A2. Overall reactivity for SCGB3A2 was observed in 116 (74.4%) of 156 primary lung cancers. SCGB3A2 was predominantly expressed in adenocarcinomas (86.5%), compared with squamous cell carcinomas (50.0%) and small cell carcinomas (42.9%). The expression in papillary adenocarcinomas was seen at higher frequency than that in tubular adenocarcinomas. There was no significant relationship between SCGB3A2 expression and tumor differentiation, and pathological stage. Positive expression of SCGB3A2 was not associated with better survival rate. SCGB3A2 expression in primary pulmonary carcinomas is high, especially in adenocarcinomas. Our results indicate that SCGB3A2 has a potential to be a specific and useful marker for primary pulmonary adenocarcinomas
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Regulation of mouse Scgb3a1 gene expression by NF-Y and association of CpG methylation with its tissue-specific expression
BMC, 2008Co-Authors: Kimura Shioko, Tomita TakeshiAbstract:Abstract Background Secretoglobin (SCGB) 3A1 is a secretory protein of small molecular weight with tumor suppressor function. It is highly expressed in lung and trachea in both human and mouse, with additional tissues expressing the protein that differ depending on the species. However, little is known about the function and transcriptional regulation of this gene in normal mouse tissues. Results By reporter gene transfection and gel mobility shift analyses, we demonstrated that expression of the mouse Scgb3a1 gene is regulated by a PU-box binding protein and a ubiquitous transcription factor NF-Y that respectively binds to the PU-boxes located at -99 to -105 bp and -158 to -164 bp, and the "CCAAT" binding sites located at -425 to -429 bp and -498 to -502 bp from the transcription start site of the gene. However, the effect of PU-box binding protein on transcriptional activation is minimal as compared to NF-Y, suggesting that NF-Y is a more critical transcription factor for mouse Scgb3a1 gene transcription. Despite that NF-Y is a ubiquitous factor, Scgb3a1 is highly expressed only in mouse lung and mtCC cells that are derived from SV40 transformed mouse Clara cells, but not in ten other mouse tissues/cells examined. Gene methylation analysis revealed that within 600 bp of the Scgb3a1 gene promoter region, there are nine CpG methylation sites present, of which two CpGs closest to the transcription start site of the gene are unmethylated in the tissues/cells expressing SCGB3A1. Conclusion A ubiquitous transcription factor NF-Y binds to and activates expression of the mouse Scgb3a1 gene and tissue-specific expression of the gene is associated with CpG methylation of the promoter.