P16 in bronchopulmonary dysplasia: Early determinant of respiratory disease?

Introduction: Bronchopulmonary dysplasia (BPD), characterized by airspace enlargement, develops in premature infants. BPD leads to persistent lung consequences in adulthood, being considered as an early determinant of adult lung diseases. P16Ink4 is a key factor implicated in aging-related lung diseases and its levels are increased in cord blood cells of preterm infants. Whether p16 is involved in BPD and its persistent consequences at the adult age remains to be determined. Aims: To determine in a mouse model of BPD: 1) if p16 deletion protects against lung alterations in new born and adult mice, and 2) if these effects are mediated by cellular senescence. Methods: Mouse pups were exposed to hyperoxia (85% O2) or room air from day 3 to 14 of life. Morphometry (mean linear intercept), elastin content (Weigert), collagen deposition (sirius red), cell senescence (βgalactosidase activity and p21) and cell proliferation (Ki67) were evaluated. Results: At day 14, hyperoxia induced airspace enlargement and cellular senescence, without modification of collagen deposition, nor cell proliferation. Hyperoxic p16-/- mice were not protected against alveolar disruption, but presented an increased alveolar wall thickness and cell proliferation. At day 60, hyperoxic mice showed persistence of airspace enlargement and senescence, without modification of collagen deposition, nor cellular proliferation. Hyperoxic p16-/- mice have reduced airspace enlargement, but increased collagen deposition, without modulation of senescence markers. Conclusions: P16 did not modulated hyperoxia-induced alveolar disruption at young age but could play a crucial role in BPD consequences in adults. This effect may be independent of cellular senescence.