Abstract Several growth factors have been associated with human bronchopulmonary dysplasia (BPD),... more Abstract Several growth factors have been associated with human bronchopulmonary dysplasia (BPD), while a select few have been shown to have a causal role in the pathogenesis of experimental BPD in a variety of animal models (mice, rat, lamb, rhesus monkey and baboon). These include connective tissue growth factor (CTGF), hypoxia-inducible factor (HIF)-1α, pulmonary hepatocyte growth factor (HGF), transforming growth factor (TGF)β1, insulin-like growth factor (IGF), and vascular endothelial growth factor (VEGF). Although inhaled nitric oxide (iNO; downstream of VEGF signaling) use had disappointing clinical outcomes when used for prevention of BPD, potential new targets involving VEGF signaling could be activation of the HIF signaling pathway either by inhibition of prolyl hydroxylase domain-containing proteins (PHDs) by using FG-4095 or by using sildenafil. Clinical evidence for a mechanistic role of other growth factors and pathways does not exist, but laboratory studies suggest potential roles for many. These include the following: the anti-TGFβ antibody ID11, curcumin, elafin and etanercept are possible future therapeutics that have not yet entered the clinical arena of BPD. Recombinant human (rh) HGF could have a possible role, though currently there are no clinical trials targeting the HGF signaling pathway. Inhibition of CTGF and/or β-catenin (using ICG001) signaling appears to hold some promise based on the experimental data. The recent report that rhIGF-1/IGFB-3 reverses the lung and pulmonary resistance changes of experimental BPD in neonatal rats and the promising results of a phase II clinical trial of the same have reawakened interest in the manipulation if IGF-1 signaling to combat BPD. Currently, the most anticipated results are those of the concomitant administration of recombinant human IGF-1 (rhIGF-1) and IGF binding protein (rhIGFBP)-3 in an ongoing clinical trial for the prevention of BPD.
Although thyroid hormone (T3) influences epithelial cell differentiation during late fetal lung d... more Although thyroid hormone (T3) influences epithelial cell differentiation during late fetal lung development, its effects on early lung morphogenesis are unknown. We hypothesized that T3 would alter...
Surfactant replacement is an effective therapy for neonatal respiratory distress syndrome. Full r... more Surfactant replacement is an effective therapy for neonatal respiratory distress syndrome. Full recovery from respiratory distress syndrome requires development of endogenous surfactant synthesis and metabolism. The influence of exogenous surfactant on the development of surfactant synthesis in premature lungs is not known. We hypothesized that different exogenous surfactants have different effects on the development of endogenous surfactant production in the premature lung. We treated organ cultures of d 25 fetal rabbit lung for 3 d with 100 mg/kg body weight of natural rabbit surfactant, Survanta, and Exosurf and measured their effects on the development of surfactant synthesis. Additional experiments tested how these surfactants and Curosurf affected surfactant protein (SP) SPA , SP-B, and SP-C mRNA expression. Surfactant synthesis was measured as the incorporation of 3 H-choline and 14 C-glycerol into disaturated phosphatidylcholine recovered from lamellar bodies. Randomized-block ANOVA showed significant differences among treatments for incorporation of both labels (p Ͻ 0.01), with natural rabbit surfactant less than control, Survanta greater than control, and Exosurf unchanged. Additional experiments with natural rabbit surfactant alone showed no significant effects in doses up to 1000 mg/kg. Survanta stimulated disaturated phosphatidylcholine synthesis (173 Ϯ 41% of control; p ϭ 0.01), increased total lamellar body disaturated phosphatidylcholine by 22% (p Ͻ 0.05), and increased 14 C-disat-PC specific activity by 35% (p Ͻ 0.05). The response to Survanta was dose-dependent up to 1000 mg/kg. Survanta did not affect surfactant release. No surfactant altered the expression of mRNA for SPA , SP-B, or SP-C. We conclude that surfactant replacement therapy can enhance the maturation of surfactant synthesis, but this potential benefit differs with different surfactant preparations. (Pediatr Res 53: 671-678, 2003) Abbreviations DPPC, dipalmitoyl phosphatidylcholine disat-PC, disaturated phosphatidylcholine LB, lamellar body NARS, natural adult rabbit surfactant PC, phosphatidylcholine PG, phosphatidylglycerol PI, phosphatidylinositol RDS, neonatal respiratory distress syndrome SPA , surfactant protein A SP-B, surfactant protein B SP-C, surfactant protein C
Long bone growth requires the precise control of chondrocyte maturation from proliferation to hyp... more Long bone growth requires the precise control of chondrocyte maturation from proliferation to hypertrophy during endochondral ossification, but the bioenergetic program that ensures normal cartilage development is still largely elusive. We show that chondrocytes have unique glucose metabolism signatures in these stages, and they undergo bioenergetic reprogramming from glycolysis to oxidative phosphorylation during maturation, accompanied by an upregulation of the pentose phosphate pathway. Inhibition of either oxidative phosphorylation or the pentose phosphate pathway in murine chondrocytes and bone organ cultures impaired hypertrophic differentiation, suggesting that the appropriate balance of these pathways is required for cartilage development. Insulin-like growth factor 2 (IGF2) deficiency resulted in a profound increase in oxidative phosphorylation in hypertrophic chondrocytes, suggesting that IGF2 is required to prevent overactive glucose metabolism and maintain a proper balance of metabolic pathways. Our results thus provide critical evidence of preference for a bioenergetic pathway in different stages of chondrocytes and highlight its importance as a fundamental mechanism in skeletal development.
The temporal origins of childhood asthma are incompletely understood. We hypothesize that allerge... more The temporal origins of childhood asthma are incompletely understood. We hypothesize that allergen sensitization which begins in early infancy causes IgE-mediated airway and vascular remodeling, and airway hyper-responsiveness. Mice were sensitized with ovalbumin (OVA) without or with anti-IgE antibody from postnatal day (P) 10 through P42. We studied airway resistance in response to Methacholine (MCh) challenge, bronchoalveolar lavage fluid (BAL) inflammatory cell content, immunohistochemistry for inflammation, alpha-smooth muscle actin (alpha-SMA) and platelet/endothelial cell adhesion molecule (PECAM) proteins, and Western blotting for vascular endothelial growth factor (VEGF) protein. Compared to controls, mice treated with OVA had increased airway resistance (baseline: 192% of control; MCH 12 mg/ mL 170% of control; P less than 0.0.5). OVA treatment also increased lung alpha-SMA, VEGF and PECAM compared to controls. Inflammatory cells in the BAL and perivascular and peribronchiolar inflammatory cell infiltrates increased over controls with OVA exposure. These changes were counteracted by anti-IgE treatment. We conclude that mice sensitized in early infancy develop an IgE-mediated hyper-reactive airway disease with airway and vascular remodeling. Preventive approaches in early infancy of at-risk individuals may reduce childhood asthma.
Chronic lung disease in prematurely born infants, defined as the need for increased inspired oxyg... more Chronic lung disease in prematurely born infants, defined as the need for increased inspired oxygen at 28 days of age, was thought to be more common in some institutions than in others. To test this hypothesis, we surveyed the experience in the intensive care nurseries at Columbia and Vanderbilt Universities, the Universities of Texas at Dallas, Washington at Seattle, and California at San Francisco, the Brigham and Women's Hospital in Boston, Texas Children's Hospital in Houston, and Mt Sinai Hospital in Toronto. The survey included 1,625 infants with birth weights of 700 to 1,500 g. We confirmed the relationship of risk to low birth weight, white race, and male sex. Significant differences in the incidence of chronic lung disease were found between institutions even when birth weight, race, and sex were taken into consideration through a multivariate logistic regression analysis. Columbia had one of the best outcomes for low birth weight infants and the lowest incidence of...
The temporal origins of childhood asthma are incompletely understood. We hypothesize that allerge... more The temporal origins of childhood asthma are incompletely understood. We hypothesize that allergen sensitization which begins in early infancy causes IgE-mediated airway and vascular remodeling, and airway hyper-responsiveness. Mice were sensitized with ovalbumin (OVA) without or with anti-IgE antibody from postnatal day (P) 10 through P42. We studied airway resistance in response to Methacholine (MCh) challenge, bronchoalveolar lavage fluid (BAL) inflammatory cell content, immunohistochemistry for inflammation, alpha-smooth muscle actin (alpha-SMA) and platelet/endothelial cell adhesion molecule (PECAM) proteins, and Western blotting for vascular endothelial growth factor (VEGF) protein. Compared to controls, mice treated with OVA had increased airway resistance (baseline: 192% of control; MCH 12 mg/ mL 170% of control; P less than 0.0.5). OVA treatment also increased lung alpha-SMA, VEGF and PECAM compared to controls. Inflammatory cells in the BAL and perivascular and peribronchiolar inflammatory cell infiltrates increased over controls with OVA exposure. These changes were counteracted by anti-IgE treatment. We conclude that mice sensitized in early infancy develop an IgE-mediated hyper-reactive airway disease with airway and vascular remodeling. Preventive
Interest in the relationship between sexual dimorphism and lung maturation emerged in the late 19... more Interest in the relationship between sexual dimorphism and lung maturation emerged in the late 1970s for one specific reason: it had been observed among pregnant women treated antenatally with glucocorticoids for lung immaturity that the risk of respiratory distress syndrome (RDS) was halved in females, but had no effect on males (1). Because of our mutual interest in fetal lung development, particularly its relationship to fetal endocrinology (2), we decided to determine the biologic basis for this phenomenon, thinking that if there were a sex-specific steroid effect, that this experiment of nature could be exploited as a means of discovering the underlying nature of the cellular machinery that mediates the processes of lung development. The global strategy we used was to exploit the spontaneous sex difference in fetal lung development that occurs across species in utero. This “tool” would allow us to tease out the clinically significant, albeit small, differences in the timing of fetal lung maturation. With the advantage of 20/20 hindsight, we should have realized that this phenomenon comprises the “small, incremental steps” that typify self-organizing systems with respect to both their ontogeny and their homeostatic control (3). Our hope was that such extensive studies would reveal the mechanisms underlying this process to better predict and prevent neonatal lung disease.
Glucocorticoid induction of pulmonary surfactant involves a mesenchymederived protein termed fibr... more Glucocorticoid induction of pulmonary surfactant involves a mesenchymederived protein termed fibroblast pneumocyte factor (FBF). This review by King and coauthors examines the evidence that keratinocyte growth factor, leptin, or neuroregulin-1β acts as FBF or components of it. See page 768
Abstract Several growth factors have been associated with human bronchopulmonary dysplasia (BPD),... more Abstract Several growth factors have been associated with human bronchopulmonary dysplasia (BPD), while a select few have been shown to have a causal role in the pathogenesis of experimental BPD in a variety of animal models (mice, rat, lamb, rhesus monkey and baboon). These include connective tissue growth factor (CTGF), hypoxia-inducible factor (HIF)-1α, pulmonary hepatocyte growth factor (HGF), transforming growth factor (TGF)β1, insulin-like growth factor (IGF), and vascular endothelial growth factor (VEGF). Although inhaled nitric oxide (iNO; downstream of VEGF signaling) use had disappointing clinical outcomes when used for prevention of BPD, potential new targets involving VEGF signaling could be activation of the HIF signaling pathway either by inhibition of prolyl hydroxylase domain-containing proteins (PHDs) by using FG-4095 or by using sildenafil. Clinical evidence for a mechanistic role of other growth factors and pathways does not exist, but laboratory studies suggest potential roles for many. These include the following: the anti-TGFβ antibody ID11, curcumin, elafin and etanercept are possible future therapeutics that have not yet entered the clinical arena of BPD. Recombinant human (rh) HGF could have a possible role, though currently there are no clinical trials targeting the HGF signaling pathway. Inhibition of CTGF and/or β-catenin (using ICG001) signaling appears to hold some promise based on the experimental data. The recent report that rhIGF-1/IGFB-3 reverses the lung and pulmonary resistance changes of experimental BPD in neonatal rats and the promising results of a phase II clinical trial of the same have reawakened interest in the manipulation if IGF-1 signaling to combat BPD. Currently, the most anticipated results are those of the concomitant administration of recombinant human IGF-1 (rhIGF-1) and IGF binding protein (rhIGFBP)-3 in an ongoing clinical trial for the prevention of BPD.
Although thyroid hormone (T3) influences epithelial cell differentiation during late fetal lung d... more Although thyroid hormone (T3) influences epithelial cell differentiation during late fetal lung development, its effects on early lung morphogenesis are unknown. We hypothesized that T3 would alter...
Surfactant replacement is an effective therapy for neonatal respiratory distress syndrome. Full r... more Surfactant replacement is an effective therapy for neonatal respiratory distress syndrome. Full recovery from respiratory distress syndrome requires development of endogenous surfactant synthesis and metabolism. The influence of exogenous surfactant on the development of surfactant synthesis in premature lungs is not known. We hypothesized that different exogenous surfactants have different effects on the development of endogenous surfactant production in the premature lung. We treated organ cultures of d 25 fetal rabbit lung for 3 d with 100 mg/kg body weight of natural rabbit surfactant, Survanta, and Exosurf and measured their effects on the development of surfactant synthesis. Additional experiments tested how these surfactants and Curosurf affected surfactant protein (SP) SPA , SP-B, and SP-C mRNA expression. Surfactant synthesis was measured as the incorporation of 3 H-choline and 14 C-glycerol into disaturated phosphatidylcholine recovered from lamellar bodies. Randomized-block ANOVA showed significant differences among treatments for incorporation of both labels (p Ͻ 0.01), with natural rabbit surfactant less than control, Survanta greater than control, and Exosurf unchanged. Additional experiments with natural rabbit surfactant alone showed no significant effects in doses up to 1000 mg/kg. Survanta stimulated disaturated phosphatidylcholine synthesis (173 Ϯ 41% of control; p ϭ 0.01), increased total lamellar body disaturated phosphatidylcholine by 22% (p Ͻ 0.05), and increased 14 C-disat-PC specific activity by 35% (p Ͻ 0.05). The response to Survanta was dose-dependent up to 1000 mg/kg. Survanta did not affect surfactant release. No surfactant altered the expression of mRNA for SPA , SP-B, or SP-C. We conclude that surfactant replacement therapy can enhance the maturation of surfactant synthesis, but this potential benefit differs with different surfactant preparations. (Pediatr Res 53: 671-678, 2003) Abbreviations DPPC, dipalmitoyl phosphatidylcholine disat-PC, disaturated phosphatidylcholine LB, lamellar body NARS, natural adult rabbit surfactant PC, phosphatidylcholine PG, phosphatidylglycerol PI, phosphatidylinositol RDS, neonatal respiratory distress syndrome SPA , surfactant protein A SP-B, surfactant protein B SP-C, surfactant protein C
Long bone growth requires the precise control of chondrocyte maturation from proliferation to hyp... more Long bone growth requires the precise control of chondrocyte maturation from proliferation to hypertrophy during endochondral ossification, but the bioenergetic program that ensures normal cartilage development is still largely elusive. We show that chondrocytes have unique glucose metabolism signatures in these stages, and they undergo bioenergetic reprogramming from glycolysis to oxidative phosphorylation during maturation, accompanied by an upregulation of the pentose phosphate pathway. Inhibition of either oxidative phosphorylation or the pentose phosphate pathway in murine chondrocytes and bone organ cultures impaired hypertrophic differentiation, suggesting that the appropriate balance of these pathways is required for cartilage development. Insulin-like growth factor 2 (IGF2) deficiency resulted in a profound increase in oxidative phosphorylation in hypertrophic chondrocytes, suggesting that IGF2 is required to prevent overactive glucose metabolism and maintain a proper balance of metabolic pathways. Our results thus provide critical evidence of preference for a bioenergetic pathway in different stages of chondrocytes and highlight its importance as a fundamental mechanism in skeletal development.
The temporal origins of childhood asthma are incompletely understood. We hypothesize that allerge... more The temporal origins of childhood asthma are incompletely understood. We hypothesize that allergen sensitization which begins in early infancy causes IgE-mediated airway and vascular remodeling, and airway hyper-responsiveness. Mice were sensitized with ovalbumin (OVA) without or with anti-IgE antibody from postnatal day (P) 10 through P42. We studied airway resistance in response to Methacholine (MCh) challenge, bronchoalveolar lavage fluid (BAL) inflammatory cell content, immunohistochemistry for inflammation, alpha-smooth muscle actin (alpha-SMA) and platelet/endothelial cell adhesion molecule (PECAM) proteins, and Western blotting for vascular endothelial growth factor (VEGF) protein. Compared to controls, mice treated with OVA had increased airway resistance (baseline: 192% of control; MCH 12 mg/ mL 170% of control; P less than 0.0.5). OVA treatment also increased lung alpha-SMA, VEGF and PECAM compared to controls. Inflammatory cells in the BAL and perivascular and peribronchiolar inflammatory cell infiltrates increased over controls with OVA exposure. These changes were counteracted by anti-IgE treatment. We conclude that mice sensitized in early infancy develop an IgE-mediated hyper-reactive airway disease with airway and vascular remodeling. Preventive approaches in early infancy of at-risk individuals may reduce childhood asthma.
Chronic lung disease in prematurely born infants, defined as the need for increased inspired oxyg... more Chronic lung disease in prematurely born infants, defined as the need for increased inspired oxygen at 28 days of age, was thought to be more common in some institutions than in others. To test this hypothesis, we surveyed the experience in the intensive care nurseries at Columbia and Vanderbilt Universities, the Universities of Texas at Dallas, Washington at Seattle, and California at San Francisco, the Brigham and Women's Hospital in Boston, Texas Children's Hospital in Houston, and Mt Sinai Hospital in Toronto. The survey included 1,625 infants with birth weights of 700 to 1,500 g. We confirmed the relationship of risk to low birth weight, white race, and male sex. Significant differences in the incidence of chronic lung disease were found between institutions even when birth weight, race, and sex were taken into consideration through a multivariate logistic regression analysis. Columbia had one of the best outcomes for low birth weight infants and the lowest incidence of...
The temporal origins of childhood asthma are incompletely understood. We hypothesize that allerge... more The temporal origins of childhood asthma are incompletely understood. We hypothesize that allergen sensitization which begins in early infancy causes IgE-mediated airway and vascular remodeling, and airway hyper-responsiveness. Mice were sensitized with ovalbumin (OVA) without or with anti-IgE antibody from postnatal day (P) 10 through P42. We studied airway resistance in response to Methacholine (MCh) challenge, bronchoalveolar lavage fluid (BAL) inflammatory cell content, immunohistochemistry for inflammation, alpha-smooth muscle actin (alpha-SMA) and platelet/endothelial cell adhesion molecule (PECAM) proteins, and Western blotting for vascular endothelial growth factor (VEGF) protein. Compared to controls, mice treated with OVA had increased airway resistance (baseline: 192% of control; MCH 12 mg/ mL 170% of control; P less than 0.0.5). OVA treatment also increased lung alpha-SMA, VEGF and PECAM compared to controls. Inflammatory cells in the BAL and perivascular and peribronchiolar inflammatory cell infiltrates increased over controls with OVA exposure. These changes were counteracted by anti-IgE treatment. We conclude that mice sensitized in early infancy develop an IgE-mediated hyper-reactive airway disease with airway and vascular remodeling. Preventive
Interest in the relationship between sexual dimorphism and lung maturation emerged in the late 19... more Interest in the relationship between sexual dimorphism and lung maturation emerged in the late 1970s for one specific reason: it had been observed among pregnant women treated antenatally with glucocorticoids for lung immaturity that the risk of respiratory distress syndrome (RDS) was halved in females, but had no effect on males (1). Because of our mutual interest in fetal lung development, particularly its relationship to fetal endocrinology (2), we decided to determine the biologic basis for this phenomenon, thinking that if there were a sex-specific steroid effect, that this experiment of nature could be exploited as a means of discovering the underlying nature of the cellular machinery that mediates the processes of lung development. The global strategy we used was to exploit the spontaneous sex difference in fetal lung development that occurs across species in utero. This “tool” would allow us to tease out the clinically significant, albeit small, differences in the timing of fetal lung maturation. With the advantage of 20/20 hindsight, we should have realized that this phenomenon comprises the “small, incremental steps” that typify self-organizing systems with respect to both their ontogeny and their homeostatic control (3). Our hope was that such extensive studies would reveal the mechanisms underlying this process to better predict and prevent neonatal lung disease.
Glucocorticoid induction of pulmonary surfactant involves a mesenchymederived protein termed fibr... more Glucocorticoid induction of pulmonary surfactant involves a mesenchymederived protein termed fibroblast pneumocyte factor (FBF). This review by King and coauthors examines the evidence that keratinocyte growth factor, leptin, or neuroregulin-1β acts as FBF or components of it. See page 768
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