Abstract
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.
Highlights
Born infants often require mechanical ventilation (MV) and/or supplemental O2, which are life-saving treatments that, elicit a chronic form of lung injury called bronchopulmonary dysplasia (BPD)
We found a significant reduction in radial alveolar count (RAC) along with an increase of the average surface area of a single alveolus and of the mean linear intercept (MLI) in lungs after HYX when compared to lungs of mice exposed to room air, indicating larger and fewer alveoli
These findings demonstrate that HYXinduced neonatal lung injury persists in adulthood, suggesting impaired repair mechanisms and reduced regenerative capacity of the lung (Figure 1A–E)
Summary
Born infants often require mechanical ventilation (MV) and/or supplemental O2, which are life-saving treatments that, elicit a chronic form of lung injury called bronchopulmonary dysplasia (BPD). BPD is characterized by reduced formation of alveoli and perturbed extracellular matrix remodeling [1,2,3]. Understanding the molecular regulation of alveolar formation and regeneration after injury is of high clinical importance in order to develop effective strategies for patients’ suffering from BPD. A recent study showed that postnatal deletion of Igf1r caused alveolar simplification and perturbed lung matrix remodeling [7]. From a cell-specific perspective, there is a growing body of evidence suggesting that IGF1 plays a role in the regulation of proliferation and differentiation of lung epithelial cells as well as fibroblasts, thereby contributing to lung repair processes [6]. Alveolar epithelial type II cells (ATIIs) are lung progenitor cells, accountable for the significant and physiological regeneration capacity of the lung. The repair of damaged alveoli is mediated via ATII–fibroblast interactions, which are tightly coordinated in lung development [9]
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