• Maéva Zysman, Baptista Bruno Ribeiro BR Univ Paris Est Creteil, INSERM, IMRB, Creteil, France. Service de Pneumologie,, Laure-Aléa Essari, Sara Taghizadeh, Charlotte Thibault de Ménonville, Clément Giffard, Amelle Issa, Marie-Laure Franco-Montoya, Marielle Breau, Rachid Souktani, Abdel Aissat, Laurence Caeymaex, Muriel Lizé, Jeanne Tran Van Nhieu, Camille Jung, Robert Rottier, Cruzeiro Marcio Do MD INSERM U1016, Institut Cochin, Paris, France. UMR 8104, Centre National de la Rech, Serge Adnot, Ralph Epaud, François Chabot, Sophie Lanone, Jorge Boczkowski, and Laurent Boyer.
• Univ Paris Est Creteil, INSERM, IMRB, Creteil, France.
• Am. J. Respir. Crit. Care Med. 2020 Oct 15; 202 (8): 1088-1104.

AbstractRationale: Promoting endogenous pulmonary regeneration is crucial after damage to restore normal lungs and prevent the onset of chronic adult lung diseases.Objectives: To investigate whether the cell-cycle inhibitor p16INK4a limits lung regeneration after newborn bronchopulmonary dysplasia (BPD), a condition characterized by the arrest of alveolar development, leading to adult sequelae.Methods: We exposed p16INK4a-/- and p16INK4aATTAC (apoptosis through targeted activation of caspase 8) transgenic mice to postnatal hyperoxia, followed by pneumonectomy of the p16INK4a-/- mice. We measured p16INK4a in blood mononuclear cells of preterm newborns, 7- to 15-year-old survivors of BPD, and the lungs of patients with BPD.Measurements and Main Results: p16INK4a concentrations increased in lung fibroblasts after hyperoxia-induced BPD in mice and persisted into adulthood. p16INK4a deficiency did not protect against hyperoxic lesions in newborn pups but promoted restoration of the lung architecture by adulthood. Curative clearance of p16INK4a-positive cells once hyperoxic lung lesions were established restored normal lungs by adulthood. p16INK4a deficiency increased neutral lipid synthesis and promoted lipofibroblast and alveolar type 2 (AT2) cell development within the stem-cell niche. Besides, lipofibroblasts support self-renewal of AT2 cells into alveolospheres. Induction with a PPARγ (peroxisome proliferator-activated receptor γ) agonist after hyperoxia also increased lipofibroblast and AT2 cell numbers and restored alveolar architecture in hyperoxia-exposed mice. After pneumonectomy, p16INK4a deficiency again led to an increase in lipofibroblast and AT2 cell numbers in the contralateral lung. Finally, we observed p16INK4a mRNA overexpression in the blood and lungs of preterm newborns, which persisted in the blood of older survivors of BPD.Conclusions: These data demonstrate the potential of targeting p16INK4a and promoting lipofibroblast development to stimulate alveolar regeneration from childhood to adulthood.

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