Intrauterine growth restriction (IUGR) and being small for gestational age (SGA) are two distinct conditions with different implications for short- and long-term child development. SGA is present if the estimated fetal or birth weight is below the tenth percentile. IUGR can be identified by additional abnormalities (pathological Doppler sonography, oligohydramnion, lack of growth in the interval, estimated weight below the third percentile) and can also be present in fetuses and neonates with weights above the tenth percentile. There is a need to differentiate between IUGR and SGA whenever possible, as IUGR in particular is associated with greater perinatal morbidity, prematurity and mortality, as well as an increased risk for diseases in later life. Recognizing fetuses and newborns being “at risk” in order to monitor them accordingly and deliver them in good time, as well as to provide adequate follow up care to ameliorate adverse sequelae is still challenging. This review article discusses approaches to differentiate IUGR from SGA and further increase diagnostic accuracy. Since adverse prenatal influences increase but individually optimized further child development decreases the risk of later diseases, we also discuss the need for interdisciplinary follow-up strategies during childhood. Moreover, we present current concepts of pathophysiology, with a focus on oxidative stress and consecutive inflammatory and metabolic changes as key molecular mechanisms of adverse sequelae, and look at future scientific opportunities and challenges. Most importantly, awareness needs to be raised that pre- and postnatal care of IUGR neonates should be regarded as a continuum.

Prematurely born infants often require supplemental oxygen that impairs lung growth and results in arrest of alveolarization and bronchopulmonary dysplasia (BPD). The growth hormone (GH)- and insulin-like growth factor (IGF)1 systems regulate cell homeostasis and organ development. Since IGF1 is decreased in preterm infants, we investigated the GH- and IGF1 signaling (1) in newborn mice with acute and prolonged exposure to hyperoxia as well as after recovery in room air; and (2) in cultured murine lung epithelial cells (MLE-12) and primary neonatal lung fibroblasts (pLFs) after treatment with GH, IGF1, and IGF1-receptor (IGF1-R) inhibitor or silencing of GH-receptor (Ghr) and Igf1r using the siRNA technique. We found that (1) early postnatal hyperoxia caused an arrest of alveolarization that persisted until adulthood. Both short-term and prolonged hyperoxia reduced GH-receptor expression and STAT5 signaling, whereas Igf1 mRNA and pAKT signaling were increased. These findings were related to a loss of epithelial cell markers (SFTPC, AQP5) and proliferation of myofibroblasts (αSMA⁺ cells). After recovery, GH-R-expression and STAT5 signaling were activated, Igf1r mRNA reduced, and SFTPC protein significantly increased. Cell culture studies showed that IGF1 induced expression of mesenchymal (e.g., Col1a1, Col4a4) and alveolar epithelial cell type I (Hopx, Igfbp2) markers, whereas inhibition of IGF1 increased SFTPC and reduced AQP5 in MLE-12. GH increased Il6 mRNA and reduced proliferation of pLFs, whereas IGF1 exhibited the opposite effect. In summary, our data demonstrate an opposite regulation of GH- and IGF1- signaling during short-term/prolonged hyperoxia-induced lung injury and recovery, affecting alveolar epithelial cell differentiation, inflammatory activation of fibroblasts, and a possible uncoupling of the GH-IGF1 axis in lungs after hyperoxia.

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.

Introduction Oxygen supplementation causes an arrest of alveolar formation and a loss of alveolar epithelial type 2 (AT2) in preterm infants, features of bronchopulmonary dysplasia (BPD). Since BDNF is a key integrator of cell homeostasis and contributes to chronic lung diseases, we now (i) performed a spatiotemporal profiling of the BDNF-signaling in neonatal mice after hyperoxia and (ii) analyzed the functional role of the BDNF receptor TrkB in AT2. Methods: (1) Wild-type mice were exposed to 85% O₂ (HYX) or 21% O₂ from birth to P28. Lungs were examined at P3-P70. (2) MLE12 cells and primary murine AT2 (mAT2) were treated with non-selective Trk inhibitor (K252a) and selective TrkB antagonist (Ana12). Results: (i) TrkB expression and phosphorylation were increased during in the alveolar phase (P7-P21), and predominantly expressed in AT2 and ACTA2+ cells. Single cell transcriptomic profiling revealed a strong expression of Bdnf in mesenchymal cells. While hyperoxia induced a 40-fold upregulation of lung Bdnf and a 3-fold elevation of serum BDNF, TrkB abundance and activation were decreased by 90%. This was related to a lower Sftpc and increased of Acta2 in lungs. (ii) Non-selective and selective blockade of TrkB reduced viability and proliferation of MLE12 and mAT2 with a loss of epithelial AT1 and AT2 markers. Discussion Our data identify an important functional role of TrkB signaling in AT2 cell homeostasis, a mechanism that is blocked in neonatal mouse lungs after hyperoxia and may contribute to a lack of regeneration and to the arrest of alveolar growth in infants with BPD, serving as a target for new therapies.

Rational: Preterm infants with mechanical ventilation (MV) often evolve bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. Our group previously showed that lung inflammation of infants with BPD leads to a loss of alveolar epithelial type 2 (AT2) cells and thus of the alveolar epithelium. We now aimed to decipher the molecular mechanisms underlying MV-induced arrest of alveolar growth and to test new therapeutic strategies. Methods: (i) Five-day-old mice underwent MV for 8h: wildtype (WT), IL6-/-, and WT with anti IL6 antibody or endothelin-1 receptor inhibitors (ET-1R). (ii) Cell culture: pulmonary microvascular endothelial cells (PMVEC), MLE12, primary AT2 from WT and FoxO1ADA mice with constitutive active FoxO1. Results: (i) Transcriptomic profiling, gene expression and protein analyses of lungs after MV revealed activation of IL6-STAT3 signaling and increased Edn1 expression, which was associated with nuclear translocation of the anti-proliferative FoxO1 in AT2. IL6-/- and pharmacologic inhibition of IL6 and ET1-R protected against nuclear trapping of pFoxO1, loss of AT2, and arrest of alveolar formation after MV. (ii) Cell culture studies: cyclic elongation and ET1 increase Il6 mRNA in MLE-12; in contrast, IL-6 induces End1 in PMVEC and MLE-12. Moreover, IL6 reduces cell survival via nuclear pFoxO1. FoxO1 knockdown improved MLE-12 survival, whereas FoxO1 overexpression reversed this effect. Finally, AT2 from FoxO1ADA mice showed reduced survival. Conclusion: Pharmacologic inhibition of IL6 and ET-1R prevents FoxO1-mediated loss of AT2 after MV and thereby opens promising therapeutic avenues for preterm infants requiring MV and at risk for BPD.

Intrauterine growth restriction (IUGR) and being born small for gestational age (SGA) are two distinct conditions with different implications for child development. IUGR is associated with greater perinatal morbidity and mortality and can be identified by additional abnormalities (pathological Doppler sonography, oligohydramnios, lack of growth in the interval, estimated weight <3rd percentile). IUGR may also be present in neonates with birth weights above the 10th percentile. Recognizing fetuses being “at risk” of a higher perinatal mortality and morbidity rate in order to monitor them accordingly and deliver them in good time is still challenging. This review article summarizes approaches to increase the diagnostic accuracy of IUGR and presents current concepts of pathophysiology with a focus on oxidative stress and consecutive inflammatory and metabolic changes. Since prenatal influences affect the risk of later diseases, we also discuss the need for interdisciplinary follow-up strategies during childhood and look at future scientific challenges. It should be emphasized that prenatal and postnatal care of IUGR neonates should be regarded as a continuum.