Altered Expressions of Fibroblast Growth Factor Receptors and Alveolarization in Neonatal Mice Exposed to 85% Oxygen

Abstract

ABSTRACT:In the present study, we tested the hypothesis that exposure of newborn mice to sublethal hyperoxia would alter lung development and expressions of fibroblast growth factor receptors (FGFRs)-3 and FGFR-4. Newborn FVB mice were exposed to 85% O 2 or maintained in room air for up to 14 d. No animal mortality was observed, and body weight gains were not affected by hyperoxia. At postnatal d 7 and 14 (P7, P14), lungs of mice exposed to 85% O 2 showed fewer alveolar secondary crests and larger alveoli or terminal air spaces than did mice in room air. In pups kept in room air, lung levels of FGFR-3 and FGFR-4 mRNA were greater at P3 than at P1, but similar increases were not observed in hyperoxic mice. Immunoreactivity of FGFR-3 and FGFR-4 was lower in lungs of hyperoxic mice than in controls at P14. In pups kept in room air, lung fibroblast growth factor (FGF)-7 mRNA levels were greater at P14 than at P1, but similar changes were not observed in hyperoxic mice. The temporally and spatially specific alterations in the expressions of FGFR-3, FGFR-4, and FGF-7 in the mice exposed to hyperoxia may contribute to aberrant lung development. B ronchopulmonary dysplasia (BPD) was described initially as lung injury-and repair-related effects that were associated with radiologic findings of streaky, fibrous densities, alternating with hyperlucent areas (1,2). The primary risk factors were premature birth, respiratory distress, mechanical ventilation, and administration of supplemental oxygen (FIO 2 Ͼ0.21). Inflammation, problems in nutritional support, and comorbid conditions also contribute to the development of BPD. Modifications of therapeutic strategies have decreased the incidence of BPD, as the disease was described originally, but the overall incidence of BPD has not declined. The "new BPD" of recent years shows little acute injury and repair described by Northway et al. (1,2), but is characterized by fewer and larger alveoli and less organized alveolar vascularization, suggesting arrested or disordered lung development. The events occurring during secondary septation of terminal gas exchange units and maturation of alveolar microvasculature are therefore of particular interest in research on mechanisms responsible for the new BPD (3-8).Lung development in humans normally progresses through sequential structural changes that are observed similarly in rats and mice, which, at term, exhibit lungs that structurally resemble human lungs at 26 -30 wk of gestation (9). Infants born at this age frequently encounter respiratory problems, arising from immature pulmonary surfactant metabolism, respiratory drive and coordination, or other deficiencies. Prematurely delivered nonhuman primate models of BPD may mimic human development more closely than do rodent models, but practical constraints limit the investigations that can be explored with primate models (4,5,10).The lungs of newborn rodents are sufficient for extrauterine life and are adequate for maturation into normal adult lungs. Studies in rats and mice indicate th...

Fibroblast Growth Factor Receptors Control Epithelial–Mesenchymal Interactions Necessary for Alveolar Elastogenesis

“…Excessive, disorganized elastic fiber accumulation can be a histopathological feature of impaired airspace formation in human bronchopulmonary dysplasia (66) and in several animal models of this disease (17,(67)(68)(69)(70). Reduced expression of FGFR3 and FGFR4 was observed in rodent models of BPD induced by neonatal hyperoxic exposure (17,18,71), suggesting that impaired alveogenesis and excessive elastic fiber accumulation observed in these models may partly result from alterations in FGFR signaling. In total, these data indicate that appropriate quantitative and spatial deposition of elastic fibers is critical for normal airspace formation and lung function.…”

RECENT RESEARCH ON THE GROWTH PLATE: Advances in fibroblast growth factor signaling in growth plate development and disorders

“…RUNX2 initiates chondrocyte hypertrophy, and loss of RUNX2 leads to severely delayed chondrocyte maturation in developing bones (Dooley et al 2007, Shinde et al 2013. Furthermore, RUNX2 expressed in the perichondrium can regulate the perichondrial expression of fibroblast growth factor 18 (FGF18) to modulate growth plate development through indirect mechanisms (Park et al 2007). RUNX2 stimulates the expression of IHH and VEGF in hypertrophic chondrocytes (Gunhaga et al 2003).…”

Fetal and postnatal lung defects reveal a novel and required role for Fgf8 in lung development

“…Importantly, deletion of both FgfR3/FgfR4 permits normal prenatal lung development but disrupts postnatal alveolar formation (Weinstein et al, 1998). More recently, additional evidence indicates that FGFR3 and 4 play important roles in regulating ECM production, secondary septation, and other aspects of both normal and pathogenic alveolar development, such as seen in infants with bronchopulmonary dysplasia (Boucherat et al, 2008; Park et al, 2007; Srisuma et al, 2010). It is unknown if FGFR1 or 2 have roles in fetal lung development, but antagonism of FGFR1 function in postnatal rats disrupts alveologenesis (Yi et al, 2006).…”