Targeting p16INK4a Promotes Lipofibroblasts and Alveolar Regeneration after Early-Life Injury.

Rationale: 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.

The normal radiological anteroposterior alignment of the lower limb in children.

INTRODUCTION: The development of reconstructive surgery of the lower limbs aimed at multilevel correction demands a precise knowledge of the physiological variations in general radiological parameters of the lower limbs in children of various age groups. It is crucial in systemic skeletal diseases, when deformities affect limbs and the surgeon does not have an intact limb as a reference. The aim of this retrospective study was to establish the normal radiological values of lower limb parameters used in the surgical correction of deformities in children of various age groups. MATERIAL AND METHODS: Teleradiographs of the lower limbs taken in children with unilateral congenital or posttraumatic deformity were retrospectively reviewed. Weight-bearing full-length anteroposterior radiographs of the entire lower extremities were taken in a standing position. The study involved 215 extremities of 208 children (93 girls and 115 boys); the ages ranged from 2 years 1 month to 15 years 11 months old. Key variables included the anatomic medial proximal femoral angle (aMPFA), anatomic lateral distal femoral angle (aLDFA), anatomic medial proximal tibial angle (aMPTA), anatomic lateral distal tibial angle (aLDTA), mechanical axis deviation (MAD), the angle formed by the femoral anatomical axis and the mechanical axis of the lower limb. RESULTS: The means and dynamics of variations, standard deviations (SD) and 95% confidence intervals of each parameter were calculated for each age and gender group. Simple regression analysis was performed to determine the relationship between the patient's age and the magnitude of aMPFA, aLDFA, aMPTA and aLDTA. Simple regression analysis showed a significant inverse correlation between patient age and the magnitude of aMPFA: the correlation coefficient was -0.77. A statistically significant inverse correlation between the MAD and the angle between the anatomic femoral axis and mechanical limb axis was found: the correlation coefficient was -0.53. CONCLUSION: In general, the received values were concordant to results of other studies. It concerned the MAD, aLDFA, aMPTA and angle between the mechanical limb axis and anatomic femoral axis. This is the first chronological evaluation of aMPFA and aLDTA from a relavively large series of patients. These normative data should be taken into consideration when evaluating lower limb alignment in children or applied in practice for planning and evaluation of the quality of surgical correction of complex deformities.