Dysregulated extracellular matrix metabolism: a basis for arrested alveolar development in bronchopulmonary dysplasia?

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Bronchopulmonary dysplasia (BPD) is a key cause of morbidity and mortality in pediatric settings. The key feature of BPD is arrested late lung development, attributed to impaired septation (division of immature alveolar airspaces into mature alveoli). The basis of this impaired septation is not understood, but preliminary observations suggest that extracellular matrix (ECM) remodeling is impaired in affected lungs. This project proposal introduces a new idea in BPD pathogenesis, where it is hypothesized that over-stabilization of the ECM impedes normal ECM remodeling, and “locks” the lung structure, making the lung resistant to normal remodeling, which might underlie the arrested development of affected lungs. The proposed project has three primary goals: (i) to assess the ECM status and expression of ECM chaperones and stabilizing enzymes in the lung in clinical and experimental BPD; (ii) to identify ECM metabolism pathways relevant to late lung development, and (iii) to identify and validate which of those pathways are dysregulated in lungs affected with BPD. The long-term objectives of this project (which extend beyond the three-year project proposed here), aim to target both the enzyme systems that direct ECM maturation, and the underlying signaling pathways controlling them, to drive proper remodeling, or indeed, reverse-remodeling of affected, immature lungs. These approaches might promote and restore normal structure to lungs affected with BPD.