Modulation of IGF-Binding Protein-2 and -3 in Hyperoxic Injury in Developing Rat Lung

Abstract

Retinoids play an important role in lung development and repair. We showed that retinoic acid (RA) inhibits O 2 -induced fibroblast proliferation in rat lung explants. IGF-1, which enhances the proliferation of human fetal lung fibroblasts and stimulates collagen production during lung injury, has an important role in the lung injury/repair process. Interactions of IGF-1 with its receptor are modulated by IGF-binding proteins IGFBPs. We hypothesized that RA alters IGFBP-2 and -3 in hyperoxiaexposed neonatal lung and alters collagen production. Neonatal rat lungs were cultured in room air or 95% O 2 and 5% CO 2 for 3 d with or without RA. IGFBP-2 and -3 were measured both in culture medium and in lung tissue. Type I collagen and procollagen propeptide were analyzed in the lung tissue. Hyperoxia induced an increase in type I collagen that was significantly inhibited in the presence of RA. IGFBP-2 and IGFBP-3 in the lungs were decreased in hyperoxia but significantly increased in hyperoxia plus RA. In the culture medium, IGFBP-2 and -3 were not increased with hyperoxia but significantly increased in the presence of RA plus hyperoxia. There was no increase in IG-FBP-3 RNA transcript after RA treatment in either room air or O 2 exposure. In conclusion, RA modulates the secreted IGFBP-2 and -3 during O 2 exposure and inhibits the increase in collagen that occurs during lung injury. We speculate that RA protects against O 2 -induced neonatal lung injury through modulation of the IGFBPs. Bronchopulmonary dysplasia (BPD) is the most common chronic pulmonary disease of premature infants who require prolonged ventilation and/or O 2 therapy, usually after the presence of respiratory distress syndrome (1). Airway hyperreactivity, which can persist for several years, is one of the long-term sequelae of BPD. Improved perinatal and neonatal care, surfactant therapy, and new ventilation modalities have had a modest impact on the incidence of BPD in very small neonates, indicating a need for greater understanding of the mechanisms that lead to BPD.Histologic features of infants who die of BPD include chronic airway inflammation and squamous metaplasia of epithelial cells in airways (2). These changes are observed in animal models of hyperoxic damage to developing lung. For example, neonatal rats that are exposed to high O 2 concentrations develop alveolar epithelial thickening as well as an increased thickness of smooth muscle (3) and interstitial matrix, with abundant myofibroblasts (4). The increase in myofibroblasts in lung tissue correlates with increased type III collagen synthesis and fibrosis (5).A recent study of biopsy and autopsy material from lungs of infants who had BPD and had received both antenatal steroids and surfactant treatment showed developmental arrest, enlarged airspaces with minimal alveolarization and variable alveolar wall cellularity, and fibrosis (6). BPD in very low birth weight infants may result from inflammatory mediators' interfering with the signaling molecules in late lung development (7). Overe...

Maternal Hyperglycemia Modifies Extracellular Matrix Signaling Pathways in Neonatal Rat Lung

“…Hyperoxia is known to induce various components of the IGF system. Paralleling our results, type I procollagen was increased with a simultaneous alteration in IGFBP-2 after hyperoxia [35] . However, these changes did not persist during the recovery phase following hyperoxia [34] .…”

“…IGF-1 enhances the proliferation of human fetal fibroblasts and stimulates collagen production [35] . The bioavailability of IGF-1 is modulated through a family of binding proteins, among which IGFBP-2 competes with the IGF-1 receptor for IGF-1.…”

Insulin-like Growth Factor-I Signaling Mechanisms, Type I Collagen and Alpha Smooth Muscle Actin in Human Fetal Lung Fibroblasts

“…Since we have shown in our earlier studies (14,15) that IGF-1 plays an important role in oxidant injury in developing lung, we chose to investigate the signaling pathway of IGF-1 in human fetal lung fibroblasts. Western blots were used to evaluate the phosphorylated form of AKT and total AKT, known also as protein kinase B (Fig.…”

“…Based on our previous studies showing that hyperoxia increased collagen synthesis in neonatal rat lung explant cultures, and also increased IGF-1 in epithelial cells (7,18), we investigated the effect of IGF-1 on Type I collagen in fetal lung fibroblasts with and without PI-3 kinase and MAP-kinase inhibitors. Figure 6 shows a representative Western blot for Type I collagen and ␤-Actin and the summary of densitometry analysis.…”

“…The production of mediators by epithelial cells in close proximity to myofibroblasts during epithelial repair after repeated damage is one possible mechanism for airway remodeling (3). IGF-1 and IGF binding proteins (IGFBPs) are active in the pulmonary cellular environment to modulate cell proliferation and function (4). IGF-1 and its receptor, IGF-1R, are also known to modulate repair processes after lung injury (5).…”