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


OBJECTIVE
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.


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.
Germano
Davide
D
Experimental Critical Care Medicine, Department of Biomedicine, University of Basel, Basel, Switzerland. davide.germano@unibas.ch
Blyszczuk
Przemyslaw
P
Valaperti
Alan
A
Kania
Gabriela
G
Dirnhofer
Stephan
S
Landmesser
Ulf
U
Lüscher
Thomas F
TF
Hunziker
Lukas
L
Zulewski
Henryk
H
Eriksson
Urs
U
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D001761:Bleomycin / Q000008:administration & dosage; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002454:Cell Differentiation / Q000276:immunology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D006023:Glycoproteins / Q000096:biosynthesis*; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D016676:Macrophages, Alveolar / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism; D010455:Peptides; D011650:Pulmonary Alveoli / Q000166:cytology / Q000276:immunology; D012038:Regeneration; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D010455:Peptides; C000606024:Prom1 protein, mouse; D001761:Bleomycin; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II