Timing and cell specificity of senescence drives postnatal lung development and injury
Hongwei Yao, Joselynn Wallace, Abigail L. Peterson, Alejandro Scaffa, Salu Rizal, Katy Hegarty, Hajime Maeda, Jason Chang, Nathalie Oulhen, Jill A. Kreiling, Kelsey E. Huntington, Monique E. De Paepe, Guilherme Barbosa, Phyllis A. Dennery
Abstract
Senescence causes age-related diseases and stress-related injury. Paradoxically, it is also essential for organismal development. Whether senescence contributes to lung development or injury in early life remains unclear. Here, we show that lung senescence occurred at birth and decreased throughout the saccular stage in mice. Reducing senescent cells at this stage disrupted lung development. In mice (<12 h old) exposed to hyperoxia during the saccular stage followed by air recovery until adulthood, lung senescence increased particularly in type II cells and secondary crest myofibroblasts. This peaked during the alveolar stage and was mediated by the p53/p21 pathway. Decreasing senescent cells during the alveolar stage attenuated hyperoxia-induced alveolar and vascular simplification. Conclusively, early programmed senescence orchestrates postnatal lung development whereas later hyperoxia-induced senescence causes lung injury through different mechanisms. This defines the ontogeny of lung senescence and provides an optimal therapeutic window for mitigating neonatal hyperoxic lung injury by inhibiting senescence.