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Research ArticlePulmonology Free access | 10.1172/JCI32526

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Jun Araya,1 Stephanie Cambier,1 Jennifer A. Markovics,1 Paul Wolters,2 David Jablons,3 Arthur Hill,3 Walter Finkbeiner,1 Kirk Jones,1 V. Courtney Broaddus,2 Dean Sheppard,2 Andrea Barzcak,2 Yuanyuan Xiao,4 David J. Erle,2 and Stephen L. Nishimura1

1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

Find articles by Xiao, Y. in: PubMed | Google Scholar

1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

Find articles by Erle, D. in: PubMed | Google Scholar

1Department of Pathology, 2Department of Medicine and Lung Biology Center, Pulmonary Division, 3Department of Surgery, and 4Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, UCSF, San Francisco, California, USA.

Address correspondence to: Stephen L. Nishimura, San Francisco General Hospital, Building 3, Room 211, 1001 Potrero Avenue, San Francisco, California 94110, USA. Phone: (415) 206-5906; Fax: (415) 206-5988; E-mail: stephen.nishimura@ucsf.edu.

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Published October 25, 2007 - More info

J Clin Invest. https://doi.org/10.1172/JCI32526.
© 2007 The American Society for Clinical Investigation
Published October 25, 2007 - Version history
Received: April 27, 2007; Accepted: August 29, 2007
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Abstract

Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1β, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-β activation in amplifying SM and driving IL-1β–dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin αvβ8, which is the major mediator of airway fibroblast TGF-β activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-β as a potential therapeutic target for COPD.

Version history
  • Version 1 (October 25, 2007): No description
  • Version 2 (November 1, 2007): No description
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