Service de Pneumologie et d'Allergologie Pédiatriques, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris, Paris, France.
Equipe 4, U955, Institut National de la Santé et de la Recherche Médicale, Créteil, France.
Am J Physiol Lung Cell Mol Physiol. 2020 Jul 1;319(1):L71-L81. doi: 10.1152/ajplung.00191.2019. Epub 2020 May 6.
SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 () was previously associated with genetic susceptibility to bronchopulmonary dysplasia in a French population of very preterm neonates. Its expression increases during lung development and is increased after exposure of rat pups to hyperoxia compared with controls bred in room air. To further investigate the role of SPOCK2 during lung development, we designed two mouse models, one that uses a specific anti-Spock2 antibody and one that reproduces the hyperoxia-induced expression with a transgenic mouse model resulting in a conditional and lung-targeted overexpression of . When mice were bred under hyperoxic conditions, treatment with anti-Spock2 antibodies significantly improved alveolarization. Lung overexpression of altered alveolar development in pups bred in room air and worsened hyperoxia-induced lesions. Neither treatment with anti-Spock2 antibody nor overexpression of was associated with abnormal activation of matrix metalloproteinase-2. These two models did not alter the expression of known players in alveolar development. This study brings strong arguments for the deleterious role of SPOCK2 on lung alveolar development especially after lung injury, suggesting its role in bronchopulmonary dysplasia susceptibility. These effects are not mediated by a deregulation in metalloproteases activity and in expression of factors essential to normal alveolarization. The balance between types 1 and 2 epithelial alveolar cells may be involved.
富含半胱氨酸的酸性分泌糖蛋白 2()曾与法国极早产儿支气管肺发育不良的遗传易感性相关。其在肺发育过程中表达增加，且在与常氧环境下饲养的对照组大鼠相比，高氧暴露后其表达增加。为了进一步研究 SPOCK2 在肺发育过程中的作用，我们设计了两种小鼠模型，一种使用特异性抗 SPOCK2 抗体，另一种通过转基因小鼠模型模拟高氧诱导的表达，从而实现条件性和肺靶向过表达。当小鼠在高氧环境下繁殖时，用抗 SPOCK2 抗体处理可显著改善肺泡化。在常氧环境下繁殖的小鼠中过表达会改变肺泡发育，并加重高氧诱导的损伤。抗 SPOCK2 抗体处理或过表达均与基质金属蛋白酶-2 的异常激活无关。这两种模型均未改变已知肺泡发育中关键因子的表达。这项研究有力地证明了 SPOCK2 在肺肺泡发育，特别是在肺损伤后的有害作用，提示其在支气管肺发育不良易感性中的作用。这些作用不是通过金属蛋白酶活性的失调或对正常肺泡化至关重要的因子的表达来介导的。1 型和 2 型上皮肺泡细胞之间的平衡可能参与其中。
