Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 306, Issue 3, Pages L246-L259Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00109.2013
Keywords
lung development; extracellular matrix; bronchopulmonary dysplasia; lysyl hydroxylase
Categories
Funding
- German Research Foundation [Mo 1789/1]
- Excellence Cluster 147 Cardio-Pulmonary System
- Federal Ministry of Higher Education, Research and the Arts of the State of Hessen LOEWE Program
- German Center for Lung Research (Deutche Lungenforschungszentrum
- all German authors)
- U. S. National Heart, Lung, and Blood Institute Grant [HL-094608]
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Bronchopulmonary dysplasia (BPD) is a common and serious complication of premature birth, characterized by a pronounced arrest of alveolar development. The underlying pathophysiological mechanisms are poorly understood although perturbations to the maturation and remodeling of the extracellular matrix (ECM) are emerging as candidate disease pathomechanisms. In this study, the expression and regulation of three members of the lysyl hydroxylase family of ECM remodeling enzymes (Plod1, Plod2, and Plod3) in clinical BPD, as well as in an experimental animal model of BPD, were addressed. All three enzymes were localized to the septal walls in developing mouse lungs, with Plod1 also expressed in the vessel walls of the developing lung and Plod3 expressed uniquely at the base of developing septa. The expression of plod1, plod2, and plod3 was upregulated in the lungs of mouse pups exposed to 85% O-2, an experimental animal model of BPD. Transforming growth factor (TGF)-beta increased plod2 mRNA levels and activated the plod2 promoter in vitro in lung epithelial cells and in lung fibroblasts. Using in vivo neutralization of TGF-beta signaling in the experimental animal model of BPD, TGF-beta was identified as the regulator of aberrant plod2 expression. PLOD2 mRNA expression was also elevated in human neonates who died with BPD or at risk for BPD, compared with neonates matched for gestational age at birth or chronological age at death. These data point to potential roles for lysyl hydroxylases in normal lung development, as well as in perturbed late lung development associated with BPD.
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