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Article ; Online: CFTR dysfunction in smooth muscle drives TGFβ dependent airway hyperreactivity.

Kramer, Elizabeth L / Hudock, Kristin M / Davidson, Cynthia R / Clancy, John P

2023 Volume 24, Issue 1, Page(s) 198

Abstract: Background: The primary underlying defect in cystic fibrosis (CF) is disrupted ion transport in epithelia throughout the body. It is unclear if symptoms such as airway hyperreactivity (AHR) and increased airway smooth muscle (ASM) volume in people with ... ...

Abstract	Background: The primary underlying defect in cystic fibrosis (CF) is disrupted ion transport in epithelia throughout the body. It is unclear if symptoms such as airway hyperreactivity (AHR) and increased airway smooth muscle (ASM) volume in people with CF are due to inherent abnormalities in smooth muscle or are secondary to epithelial dysfunction. Transforming Growth Factor beta 1 (TGFβ) is an established genetic modifier of CF lung disease and a known driver of abnormal ASM function. Prior studies have demonstrated that CF mice develop greater AHR, goblet cell hyperplasia, and ASM hypertrophy after pulmonary TGFβ exposure. However, the mechanism driving these abnormalities in CF lung disease, specifically the contribution of CFTR loss in ASM, was unknown. Methods: In this study, mice with smooth muscle-specific loss of CFTR function (Cftr Results: Cftr Conclusions: These results demonstrate a direct smooth muscle contribution to CF airway obstruction mediated by TGFβ. Dysfunction in non-epithelial tissues should be considered in the development of CF therapeutics, including potential genetic therapies.
MeSH term(s)	Animals ; Mice ; Asthma ; Cystic Fibrosis/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Hyperplasia/metabolism ; Hyperplasia/pathology ; Muscle, Smooth/metabolism ; Transforming Growth Factor beta/metabolism
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Transforming Growth Factor beta ; Cftr protein, mouse
Language	English
Publishing date	2023-08-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2041675-1
ISSN	1465-993X ; 1465-993X
ISSN (online)	1465-993X
ISSN	1465-993X
DOI	10.1186/s12931-023-02495-2
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Article ; Online: Subacute TGFβ Exposure Drives Airway Hyperresponsiveness in Cystic Fibrosis Mice through the PI3K Pathway.

Kramer, Elizabeth L / Madala, Satish K / Hudock, Kristin M / Davidson, Cynthia / Clancy, John P

American journal of respiratory cell and molecular biology

2020 Volume 62, Issue 5, Page(s) 657–667

Abstract: Cystic fibrosis (CF) is a lethal genetic disease characterized by progressive lung damage and airway obstruction. The majority of patients demonstrate airway hyperresponsiveness (AHR), which is associated with more rapid lung function decline. Recent ... ...

Abstract	Cystic fibrosis (CF) is a lethal genetic disease characterized by progressive lung damage and airway obstruction. The majority of patients demonstrate airway hyperresponsiveness (AHR), which is associated with more rapid lung function decline. Recent studies in the neonatal CF pig demonstrated airway smooth muscle (ASM) dysfunction. These findings, combined with observed CF transmembrane conductance regulator (CFTR) expression in ASM, suggest that a fundamental defect in ASM function contributes to lung function decline in CF. One established driver of AHR and ASM dysfunction is transforming growth factor (TGF) β1, a genetic modifier of CF lung disease. Prior studies demonstrated that TGFβ exposure in CF mice drives features of CF lung disease, including goblet cell hyperplasia and abnormal lung mechanics. CF mice displayed aberrant responses to pulmonary TGFβ, with elevated PI3K signaling and greater increases in lung resistance compared with controls. Here, we show that TGFβ drives abnormalities in CF ASM structure and function through PI3K signaling that is enhanced in CFTR-deficient lungs. CF and non-CF mice were exposed intratracheally to an adenoviral vector containing the TGFβ1 cDNA, empty vector, or PBS only. We assessed methacholine-induced AHR, bronchodilator response, and ASM area in control and CF mice. Notably, CF mice demonstrated enhanced AHR and bronchodilator response with greater ASM area increases compared with non-CF mice. Furthermore, therapeutic inhibition of PI3K signaling mitigated the TGFβ-induced AHR and goblet cell hyperplasia in CF mice. These results highlight a latent AHR phenotype in CFTR deficiency that is enhanced through TGFβ-induced PI3K signaling.
MeSH term(s)	Adrenergic beta-Agonists/pharmacology ; Albuterol/pharmacology ; Animals ; Bronchoconstriction/drug effects ; Cystic Fibrosis/enzymology ; Cystic Fibrosis/physiopathology ; Goblet Cells/pathology ; Hyperplasia ; Lung/physiopathology ; Mice, Inbred C57BL ; Muscle, Smooth/drug effects ; Muscle, Smooth/physiopathology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors/pharmacology ; Respiratory Hypersensitivity/enzymology ; Respiratory Hypersensitivity/physiopathology ; Signal Transduction/drug effects ; Transforming Growth Factor beta/adverse effects
Chemical Substances	Adrenergic beta-Agonists ; Phosphoinositide-3 Kinase Inhibitors ; Transforming Growth Factor beta ; Albuterol (QF8SVZ843E)
Language	English
Publishing date	2020-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2019-0158OC
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Article ; Online: Subacute TGFβ expression drives inflammation, goblet cell hyperplasia, and pulmonary function abnormalities in mice with effects dependent on CFTR function.

Kramer, Elizabeth L / Hardie, William D / Madala, Satish K / Davidson, Cynthia / Clancy, John P

American journal of physiology. Lung cellular and molecular physiology

2018 Volume 315, Issue 3, Page(s) L456–L465

Abstract: Cystic fibrosis (CF) produces variable lung disease phenotypes that are, in part, independent of the CF transmembrane conductance regulator ( CFTR) genotype. Transforming growth factor-β (TGFβ) is the best described genetic modifier of the CF phenotype, ... ...

Abstract	Cystic fibrosis (CF) produces variable lung disease phenotypes that are, in part, independent of the CF transmembrane conductance regulator ( CFTR) genotype. Transforming growth factor-β (TGFβ) is the best described genetic modifier of the CF phenotype, but its mechanism of action is unknown. We hypothesized that TGFβ is sufficient to drive pathognomonic features of CF lung disease in vivo and that CFTR deficiency enhances susceptibility to pathological TGFβ effects. A CF mouse model and littermate controls were exposed intratracheally to an adenoviral vector containing the TGFβ1 cDNA (Ad-TGFβ), empty vector, or PBS only. Studies were performed 1 wk after treatment, including lung mechanics, collection of bronchoalveolar lavage fluid, and analysis of lung histology, RNA, and protein. CF and non-CF mice showed similar weight loss, inflammation, goblet cell hyperplasia, and Smad pathway activation after Ad-TGFβ treatment. Ad-TGFβ produced greater abnormalities in lung mechanics in CF versus control mice, which was uniquely associated with induction of phosphoinositide 3-kinase and mitogen-activated protein kinase signaling. CFTR transcripts were reduced, and epithelial sodium channel transcripts were increased in CF and non-CF mice, whereas the goblet cell transcription factors, forkhead ortholog A3 and SAM-pointed domain-containing ETS-like factor, were increased in non-CF but not CF mice following Ad-TGFβ treatment. Pulmonary TGFβ1 expression was sufficient to produce pulmonary remodeling and abnormalities in lung mechanics that were associated with both shared and unique cell signaling pathway activation in CF and non-CF mice. These results highlight the multifunctional impact of TGFβ on pulmonary pathology in vivo and identify cellular-response differences that may impact CF lung pathology.
MeSH term(s)	Adenoviridae ; Animals ; Cystic Fibrosis/genetics ; Cystic Fibrosis/metabolism ; Cystic Fibrosis/pathology ; Cystic Fibrosis/physiopathology ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Gene Expression Regulation ; Goblet Cells/metabolism ; Goblet Cells/pathology ; Hyperplasia ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/pathology ; Lung/metabolism ; Lung/pathology ; Lung/physiopathology ; Mice ; Mice, Transgenic ; Transduction, Genetic ; Transforming Growth Factor beta1/biosynthesis ; Transforming Growth Factor beta1/genetics
Chemical Substances	Cftr protein, mouse ; Tgfb1 protein, mouse ; Transforming Growth Factor beta1 ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2018-06-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00530.2017
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Uc I Zs.89: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.A 2749: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Longitudinal free-breathing MRI measurement of murine lung physiology in a progressive model of lung fibrosis.

Guo, Jinbang / Hardie, William D / Cleveland, Zackary I / Davidson, Cynthia / Xu, Xuefeng / Madala, Satish K / Woods, Jason C

Journal of applied physiology (Bethesda, Md. : 1985)

2019 Volume 126, Issue 4, Page(s) 1138–1149

Abstract: To longitudinally monitor progressive fibrosis in the transforming growth factor-α (TGF-α) transgenic mouse model of lung fibrosis, we used retrospective self-gating ultrashort echo time (UTE) magnetic resonance imaging (MRI) to image mouse lung at ... ...

Abstract	To longitudinally monitor progressive fibrosis in the transforming growth factor-α (TGF-α) transgenic mouse model of lung fibrosis, we used retrospective self-gating ultrashort echo time (UTE) magnetic resonance imaging (MRI) to image mouse lung at baseline and after 4 and 8 wk of fibrosis initiation via doxycycline administration. Only bitransgenic mice were used in this study and divided into two cohorts: six mice were fed doxycycline food to induce lung fibrosis (referred to as Dox cohort), and five other mice were fed normal food (referred to as control cohort). Lung mechanics, histology, and hydroxyproline were assessed after the final MRI. A linear mixed-effects model was used to analyze MRI-derived longitudinal lung-function parameters. Tidal volume decreased at a rate of -0.016 ± 0.002 ml/week [χ
MeSH term(s)	Animals ; Disease Models, Animal ; Disease Progression ; Female ; Hydroxyproline/metabolism ; Image Interpretation, Computer-Assisted/methods ; Imaging, Three-Dimensional/methods ; Longitudinal Studies ; Lung/metabolism ; Lung/physiopathology ; Magnetic Resonance Imaging/methods ; Male ; Mice ; Mice, Transgenic ; Pulmonary Fibrosis/metabolism ; Pulmonary Fibrosis/physiopathology ; Respiration ; Respiratory Function Tests/methods ; Retrospective Studies ; Transforming Growth Factor alpha/metabolism
Chemical Substances	Transforming Growth Factor alpha ; Hydroxyproline (RMB44WO89X)
Language	English
Publishing date	2019-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	219139-8
ISSN	1522-1601 ; 0021-8987 ; 0161-7567 ; 8750-7587
ISSN (online)	1522-1601
ISSN	0021-8987 ; 0161-7567 ; 8750-7587
DOI	10.1152/japplphysiol.00993.2018
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Article ; Online: Unique and Redundant Functions of p70 Ribosomal S6 Kinase Isoforms Regulate Mesenchymal Cell Proliferation and Migration in Pulmonary Fibrosis.

Madala, Satish K / Sontake, Vishwaraj / Edukulla, Ramakrishna / Davidson, Cynthia R / Schmidt, Stephanie / Hardie, William D

American journal of respiratory cell and molecular biology

2016 Volume 55, Issue 6, Page(s) 792–803

Abstract: The p70 ribosomal S6 kinase (p70S6K) is a downstream substrate that is phosphorylated and activated by the mammalian target of rapamycin complex and regulates multiple cellular processes associated with pulmonary fibrogenesis. Two isoforms of the p70S6K ... ...

Abstract	The p70 ribosomal S6 kinase (p70S6K) is a downstream substrate that is phosphorylated and activated by the mammalian target of rapamycin complex and regulates multiple cellular processes associated with pulmonary fibrogenesis. Two isoforms of the p70S6K have been identified (S6K1 and S6K2), but their relative contributions in mediating pulmonary fibrosis are unknown. To interrogate the roles of the p70S6K isoforms, we overexpressed transforming growth factor (TGF)-α in mice deficient for the S6K1 or S6K2 genes and measured changes in lung histology, morphometry, total lung collagen, lung function, and proliferation between wild-type and isoform-deficient mice. Deficiency of S6K1, but not S6K2, had a significant effect on reducing proliferation in subpleural fibrotic lesions during TGF-α-induced fibrosis. Migration was significantly decreased in mesenchymal cells isolated from the lungs of S6K1 knockout mice compared with wild-type or S6K2 knockout mice. Conversely, increases in subpleural thickening were significantly decreased in S6K2-deficient mice compared with wild type. Deficiency of S6K2 significantly reduced phosphorylation of the downstream S6 ribosomal protein in lung homogenates and isolated mesenchymal cells after TGF-α expression. However, deficiency of neither isoform alone significantly altered TGF-α-induced collagen accumulation or lung function decline in vivo. Furthermore, deficiency in neither isoform prevented changes in collagen accumulation or lung compliance decline after administration of intradermal bleomycin. Together, these findings demonstrate that the p70S6K isoforms have unique and redundant functions in mediating fibrogenic processes, including proliferation, migration, and S6 phosphorylation, signifying that both isoforms must be targeted to modulate p70S6K-mediated pulmonary fibrosis.
MeSH term(s)	Animals ; Bleomycin ; Cell Movement ; Cell Proliferation ; Collagen/metabolism ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Humans ; Isoenzymes/metabolism ; Ki-67 Antigen/metabolism ; Lung/metabolism ; Lung/pathology ; Lung/physiopathology ; Mesoderm/pathology ; Mice, Transgenic ; Phosphorylation ; Pulmonary Fibrosis/enzymology ; Pulmonary Fibrosis/pathology ; Pulmonary Fibrosis/physiopathology ; Ribosomal Protein S6 Kinases, 70-kDa/deficiency ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Signal Transduction ; Transforming Growth Factor alpha/metabolism
Chemical Substances	Isoenzymes ; Ki-67 Antigen ; Transforming Growth Factor alpha ; Bleomycin (11056-06-7) ; Collagen (9007-34-5) ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1)
Language	English
Publishing date	2016-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2016-0090OC
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Book ; Conference proceedings: Anything

Davidson, Cynthia C

[documents the final conference, Anything, which took place on June 1, 2, 3, 2000, at the Solomon R. Guggenheim Museum in New York City]

(Any ; : [books and conferences of the 11-year program] / Anyone Corporation ; 10)

2001

Institution	Anyone Corporation Anything Conference Solomon R. Guggenheim Museum
Event/congress	Anything Conference (NewYork2000.07.1-3)
Author's details	ed. by Cynthia C. Davidson
Series title	Any ; : [books and conferences of the 11-year program] / Anyone Corporation ; 10
Language	English
Size	283 S, zahlr. Ill
Publisher	MIT Press ; Anyone Corp
Publishing place	Cambridge, Mass ; New York, N.Y
Document type	Book ; Conference proceedings
Note	Anything is the tenth in a series of ten planned volumes documenting the annual international, cross-disciplinary conferences being sponsored by the Anyone Corporation to investigate the condition of architecture at the end of the millennium"--T.p. verso ; Includes bibliographical references
ISBN	0262541300 ; 9780262541305
Database	Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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Book: Tradition and invention in architecture

Stern, Robert A. M / Davidson, Cynthia

conversations and essays

2011

Abstract: Among practicing architects today, perhaps only Robert A. M. Stern once contemplated a career as a historian, an interest that has informed both his built work and his writings. Tradition and Invention in Architecture brings together 26 of Stern's essays ...

Author's details	Robert A. M. Stern. Ed. by Cynthia Davidson
Abstract	Among practicing architects today, perhaps only Robert A. M. Stern once contemplated a career as a historian, an interest that has informed both his built work and his writings. Tradition and Invention in Architecture brings together 26 of Stern's essays and conversations from the past five decades. Topics range from modern classicism, American housing, gardens, and New York City to the work of Norman Foster, Louis Kahn, Charles Moore, and Robert Moses. Reminders of Stern's own broad career in architecture are found in his thoughts on his PBS television series Pride of Place, his discussion of the planning of Seaside and Celebration, Florida, and his view on institutional branding through architecture. Known as much for his candor as for his profound knowledge of American architecture, Stern's observations on the architecture of his time are equally valuable. As he writes, "For an architect, writing is one way of reconsidering history while working in the present--always in search of the best from the past and the present, which allows us to invent for the future
Keywords	Architectural design ; Influence (Literary, artistic, etc.)
Language	English
Size	[IX], 189 S., zahlr. Ill., graph. Darst., Kt.
Publisher	Yale University Press
Publishing place	New Haven, Conn. u.a.
Document type	Book
Note	Includes bibliographical references and index
ISBN	9780300181159 ; 0300181159
Database	Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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Book ; Conference proceedings: Anymore

Davidson, Cynthia C

(Any ; : [books and conferences of the 11-year program] / Anyone Corporation ; 9)

2000

Institution	Anymore Conference Anyone Corporation
Event/congress	Anymore Conference (1999.06.23-25, Paris)
Author's details	[Anymore Conference, Paris, June 23 - 25, 1999]. Ed. by Cynthia Davidson
Series title	Any ; : [books and conferences of the 11-year program] / Anyone Corporation ; 9
Language	English
Size	295 S, Ill, 27 cm
Publisher	MIT Press
Publishing place	Cambridge, Mass. u.a.
Document type	Book ; Conference proceedings
ISBN	0262541106 ; 9780262541107
Database	Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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Book: Far from Equilibrium

Kwinter, Sanford / Davidson, Cynthia

essays on technology and design culture

2007

Author's details	Sanford Kwinter. Ed. by Cynthia Davidson
Language	English
Size	191 S., Ill., 24 cm
Publisher	ACTAR
Publishing place	Barcelona
Document type	Book
Note	Collected essays, partly already publ ; Includes bibliographical references ; Text in English
ISBN	9788496540644 ; 8496540642
Database	Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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Book: Anytime

Davidson, Cynthia C

1999

Author's details	edited by Cynthia Davidson
Keywords	Architecture, Modern/Themes, motives ; Space (Architecture)
Language	English
Size	296 S, Ill, 27cm
Publisher	MIT Press
Publishing place	Cambridge, Mass. u.a.
Document type	Book
ISBN	0262541025 ; 9780262541022
Database	Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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