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Prominin-1/CD133+ lung epithelial progenitors protect from bleomycin-induced pulmonary fibrosis

Germano, Davide and Blyszczuk, Przemyslaw and Valaperti, Alan and Kania, Gabriela and Dirnhofer, Stephan and Landmesser, Ulf and Lüscher, Thomas F. and Hunziker, Lukas and Zulewski, Henryk and Eriksson, Urs. (2009) Prominin-1/CD133+ lung epithelial progenitors protect from bleomycin-induced pulmonary fibrosis. American journal of respiratory and critical care medicine : an official journal of the American Thoracic Society, Vol. 179. pp. 939-949.

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Official URL: http://edoc.unibas.ch/dok/A6003173

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Abstract

RATIONALE: The mouse model of bleomycin-induced lung injury offers an approach to study idiopathic pulmonary fibrosis, a progressive interstitial lung disease with poor prognosis. Progenitor cell-based treatment strategies might combine antiinflammatory effects and the capacity for tissue repair. OBJECTIVES: To expand progenitor cells with reparative and regenerative capacities and to evaluate their protective effects on pulmonary fibrosis in vivo. METHODS: Prominin-1/CD133(+) epithelial progenitor cells (PEPs) were expanded from adult mouse lungs after digestion and culture of distal airways. Lung fibrosis was induced in C57Bl/6 mice by instillation of bleomycin. Two hours later, animals were transplanted with PEPs. Inflammation and fibrosis were assessed by immunohistochemistry, bronchoalveolar lavage fluid differentials, and real-time polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: PEPs expanded from mouse lungs were of bone marrow origin, coexpressed stem and hematopoietic cell markers, and differentiated in vitro into alveolar type II surfactant protein-C(+) epithelial cells. In bleomycin-challenged mice, intratracheally injected PEPs engrafted into the lungs and differentiated into type II pneumocytes. Furthermore, PEPs suppressed proinflammatory and profibrotic gene expression, prevented the recruitment of inflammatory cells, and protected bleomycin-challenged mice from pulmonary fibrosis. Mechanistically, the protective effect depended on upregulation of inducible nitric oxide synthase in PEPs and nitric oxide-mediated suppression of alveolar macrophage proliferation. Accordingly, PEPs from iNOS(-/-) but not iNOS(+/+) mice failed to protect from bleomycin-induced lung injury. CONCLUSIONS: The combined antiinflammatory and regenerative capacity of bone marrow-derived pulmonary epithelial progenitors offers a promising approach for development of cell-based therapeutic strategies against pulmonary fibrosis.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB
03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Endokrinologie / Diabetologie
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Endokrinologie / Diabetologie
03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Histopathologie (Dirnhofer)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Histopathologie (Dirnhofer)
UniBasel Contributors:Dirnhofer, Stephan and Eriksson, Urs and Zulewski, Henryk
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Thoracic Society
ISSN:0003-0805
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Feb 2013 08:46
Deposited On:01 Feb 2013 08:42

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