458 - Cellular senescence paradoxically drives postnatal lung development and injury in mice

Poster Number: 458
Publication Number: 458.432

Hongwei Yao, Brown University, Providence, RI, United States; Abigail L. Peterson, The Warren Alpert Medical School of Brown University, Providence, RI, United States; Salu Rizal, University of New Haven, Somerville, MA, United States; Jason Chang, Brown University, Providence, RI, United States; Phyllis Dennery, The Warren Alpert Medical School of Brown University, Providence, RI, United States

Background: Cellular senescence has been demonstrated in aging, age-related diseases and stress-related injury. Paradoxically, it is also essential for organismal development across evolutionary distant vertebrates. Whether senescence contributes to lung development or injury in early life remains unknown.

Objective: We hypothesized that senescence participates in postnatal lung development, and that this is abnormally enhanced with hyperoxic exposure, leading to alveolar simplification.

Design/Methods: Senescence biomarkers, including SA-β-gal and loss of nuclear lamin b1, were measured in the lung of newborn mice at postnatal day (pnd) 0 until pnd60 under normoxic condition. Lung senescence was also evaluated in C57BL/6J mice ( < 12 h old) exposed to hyperoxia (>95% O2) for 3 days during the saccular stage of lung development followed by air recovery until adulthood. We employed p21 knockout mice (C57BL/6J background) and a specific p21 inhibitor UC2288 (2 and 5 mg/kg, i.p.) to determine the pathways underlying lung developmental and hyperoxia-induced senescence. A senolytic cocktail quercetin/dasatinib (2.5 and 5 mg/kg, i.p.) was administered into mice at the saccular or alveolar stage to evaluate the role of senescence in lung development and hyperoxic lung injury, using the mean linear intercept (Lm) and radial alveolar counts (RAC).

Results: Lung senescence peaked at birth and dramatically decreased throughout the saccular stage in mice. Removing senescent cells early in postnatal life, using the senolytic cocktail quercetin/dasatinib at pnd1 and pnd3 or via embryonic p21 deletion, disrupted lung development. In contrast, in mice exposed to hyperoxia during the saccular stage followed by air recovery until adulthood, lung senescence increased at pnd7, compared to air controls, particularly in type II cells. This was mediated by the p53/p21 pathway. Eliminating senescent cells during the alveolar stage at pnd4 and pnd6, using quercetin/dasatinib or UC2288, inhibited hyperoxia-induced alveolar simplification.Conclusion(s): Early programmed senescence orchestrates postnatal lung development whereas later hyperoxia-induced senescence causes alveolar simplification. This work defines the ontogeny of lung senescence and provides an optimal therapeutic window for clearing senescent cells to mitigate neonatal hyperoxic lung injury and bronchopulmonary dysplasia.