Abstract
We have taken a basic biologic approach to elucidate the pathophysiology of bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, based on cell/molecular mechanisms of physiologic lung development. Stretch coordinates parathyroid hormone-related protein (PTHrP) signaling between the alveolar type II cell and the mesoderm to coordinately up-regulate key genes for the homeostatic fibroblast phenotype- including peroxisome proliferator activated receptor gamma (PPARĪ³), adipocyte differentiation related protein (ADRP), and leptin- and the retrograde stimulation of type II cell surfactant synthesis by leptin. Each of these paracrine interactions requires cell-specific receptors on adjacent cells derived from the mesoderm or endoderm, respectively, to serially up-regulate the signaling pathways between and within each cell-type. It is this functional compartmentation that is key to understanding how specific agonists and antagonists can predictably affect this mechanism of alveolar homeostasis. Using a wide variety of pathophysiologic insults associated with BPD- barotrauma, oxotrauma, and infection, we have found that there are type II cell and/or fibroblast cell/molecular effects generated by these insults, which can lead to the BPD phenotype. We have exploited these cell-specific mechanisms to effectively prevent and treat lung injuries using PPARĪ³ agonists to sustain this signaling pathway. It is critically important to judiciously select physiologically and developmentally relevant interventions when treating the preterm neonate.
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Abbreviations
- ADRP:
-
adipocyte differentiation related protein
- Ī±SMA:
-
alpha smooth muscle actin
- BPD:
-
bronchopulmonary dysplasia
- FRLF:
-
fetal rat lung fibroblast
- PGJ2:
-
prostaglandin J2
- PPARĪ³:
-
peroxisome proliferator activated receptor gamma
- RGZ:
-
rosiglitazone
- VLBWI:
-
very low birth weight infant
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This work was supported by grants from the American Heart Association (grant no. 0265127), the National Institutes of Health (grant nos. HL55268 and HL75405), the March of Dimes Foundation, Philip Morris USA Inc. and Philip Morris International, and the Tobacco-Related Disease Research Program (grant nos. 14RT-0073 and 15IT-0250).
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Torday, J., Rehan, V. Developmental Cell/Molecular Biologic Approach to the Etiology and Treatment of Bronchopulmonary Dysplasia. Pediatr Res 62, 2ā7 (2007). https://doi.org/10.1203/PDR.0b013e31806772a1
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DOI: https://doi.org/10.1203/PDR.0b013e31806772a1
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