Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, 575 Children's Cross Road, Columbus, OH, USA.
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
Respir Res. 2018 Nov 21;19(1):229. doi: 10.1186/s12931-018-0938-1.
Hyperoxia is a frequently employed therapy for prematurely born infants, induces lung injury and contributes to development of bronchopulmonary dysplasia (BPD). BPD is characterized by decreased cellular proliferation, cellular migration, and failure of injury repair systems. Actin binding proteins (ABPs) such as VASP, cofilin1, and profilin1 regulate cell proliferation and migration via modulation of actin dynamics. Lung mesenchymal stem cells (L-MSCs) initiate repair processes by proliferating, migrating, and localizing to sites of injury. These processes have not been extensively explored in hyperoxia induced lung injury and repair.
ABPs and CD146 L-MSCs were analyzed by immunofluorescence in human lung autopsy tissues from infants with and without BPD and by western blot in lung tissue homogenates obtained from our murine model of newborn hyperoxic lung injury.
Decreased F-actin content, ratio of VASP, and profilin 1 expression were observed in human lung tissues but this same pattern was not observed in lungs from hyperoxia-exposed newborn mice. Increases in cofilin1 expression were observed in both human and mouse tissues at 7d indicating a dysregulation in actin dynamics which may be related to altered growth. CD146 levels were elevated in human and newborn mice tissues (7d).
Altered phosphorylation of VASP and expression of profilin 1 and cofilin 1 in human tissues indicate that the pathophysiology of BPD involves dysregulation of actin binding proteins. Lack of similar changes in a mouse model of hyperoxia exposure imply that disruption in actin binding protein expression may be linked to interventions or morbidities other than hyperoxia alone.
高氧是早产儿常用的治疗方法，会导致肺损伤，并导致支气管肺发育不良（BPD）的发生。BPD 的特征是细胞增殖减少、细胞迁移减少以及损伤修复系统失效。肌动蛋白结合蛋白（ABPs）如 VASP、原肌球蛋白 1 和丝状肌动蛋白 1 通过调节肌动蛋白动力学来调节细胞增殖和迁移。肺间充质干细胞（L-MSCs）通过增殖、迁移和定位到损伤部位来启动修复过程。这些过程在高氧诱导的肺损伤和修复中尚未得到广泛研究。
通过免疫荧光分析来自有或无 BPD 的婴儿肺尸检组织中的 ABPs 和 CD146 L-MSCs，并通过 Western blot 分析从我们的新生高氧肺损伤小鼠模型中获得的肺组织匀浆中的 ABPs 和 CD146 L-MSCs。
在人肺组织中观察到 F-肌动蛋白含量、VASP 和丝状肌动蛋白 1 表达的减少，但在高氧暴露的新生小鼠肺中未观察到相同的模式。在人组织和小鼠组织中均观察到 7d 时 cofilin1 表达增加，表明肌动蛋白动力学发生紊乱，这可能与生长改变有关。CD146 水平在人组织和新生小鼠组织中升高（7d）。
人组织中 VASP 的磷酸化以及丝状肌动蛋白 1 和 cofilin 1 的表达改变表明，BPD 的病理生理学涉及肌动蛋白结合蛋白的失调。在高氧暴露的小鼠模型中没有观察到类似的变化，这表明肌动蛋白结合蛋白表达的中断可能与除高氧以外的干预或病态有关。
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