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

在儿科环境中，支气管肺发育不良(BPD)是导致发病率和死亡率的主要原因。BPD的主要特征是肺发育迟缓，归因于肺间隔受损(将未成熟的肺泡划分为成熟的肺泡)。这种间隔受损的基础尚不清楚，但初步观察表明，在受影响的肺中，细胞外基质(ECM)重塑受到损害。本项目提案在BPD的发病机制中引入了一个新的概念，假设ECM的过度稳定阻碍了正常的ECM重塑，并“锁定”了肺结构，使肺对正常重塑产生抵抗，这可能是受影响肺发育受阻的原因。拟议的项目有三个主要目标：(I)评估临床和实验性BPD患者肺内ECM的状态和ECM伴侣和稳定酶的表达；(Ii)确定与肺发育后期相关的ECM代谢途径；以及(Iii)识别和验证其中哪些途径在BPD患者的肺中调节失调。该项目的长期目标(超出这里提出的为期三年的项目)旨在针对引导ECM成熟的酶系统和控制它们的潜在信号通路，以推动受影响的未成熟肺的适当重塑，甚至是反向重塑。这些方法可能促进和恢复受BPD影响的肺的正常结构。

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.