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...
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...
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.
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...
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...
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.
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