Submitted on January 25, 2007
Accepted on June 5, 2007
Poly(ADP-ribose) polymerase-1 (PARP-1) controls lung cell proliferation and repair after hyperoxia-induced lung damage
Alessandra Pagano1*, Isabelle Metrailler-Ruchonnet1, Michel Aurrand-Lions2, Monica Lucattelli3, Yves Donati1, and Constance Barazzone-Argiroffo1
1 Pathology-Immunology and Pediatrics, Medical School, University of Geneva, geneva, Switzerland
2 Patholgy and Immunology, Medical School, University of Geneva, Geneva, Switzerland
3 Physiopathology and Experimental Medicine, University of Siena, Siena, Italy
* To whom correspondence should be addressed. E-mail: alessandra.pagano{at}medecine.unige.ch.
Oxygen-based therapies expose lung to elevated levels of ROS and induce lung cell damage and inflammation. Injured cells are replaced through increased proliferation and differentiation of epithelial cells and fibroblasts. Failure to modulate these processes leads to excessive cell proliferation, collagen deposition, fibrosis and chronic lung disease. Poly(ADP-ribose) polymerase-1 (PARP-1) is activated in response to DNA damage and participates in DNA repair, genomic integrity and cell death. In this study, we evaluated the role of PARP-1 in lung repair during recovery after acute hyperoxia exposure. We exposed PARP-1 -/- and wild-type mice for 64 h to 100% hyperoxia and let them recover in air for 5 to 21 days. PARP-1 deficient mice exhibited significantly higher lung cell hyperplasia and proliferation than PARP-1 +/+ animals after 5 and 10 days of recovery. This was accompanied by an increased inflammatory response in PARP-1 -/- compared to wild-type animals, characterized by lung neutrophil infiltration and increased IL-6 levels in broncho-alveolar lavages. These lesions were reversible, since the extent of the hyperplastic regions was reduced after 21 days of recovery and did not result in fibrosis. In vitro, lung primary fibroblasts derived from PARP-1 -/- mice showed higher proliferative response than PARP-1 +/+ cells during air recovery, after hyperoxia-induced growth arrest. All together, these results reveal an essential role of PARP-1 in the control of cell repair and tissue remodeling after hyperoxia-induced lung injury.
