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


Germano, D; Blyszczuk, P; Valaperti, A; Kania, G; Dirnhofer, S; Landmesser, U; Lüscher, T F; Hunziker, L; Zulewski, H; Eriksson, U (2009). Prominin-1/CD133+ lung epithelial progenitors protect from bleomycin-induced pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 179(10):939-949.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:15 May 2009
Deposited On:25 Aug 2009 11:09
Last Modified:05 Apr 2016 13:20
Publisher:American Thoracic Society
ISSN:1073-449X
Publisher DOI:10.1164/rccm.200809-1390OC
PubMed ID:19234103
Permanent URL: http://doi.org/10.5167/uzh-20357

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