Division of Biology and Medicine, Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, SFH, Providence, RI, 02912, USA.
Department of Respiratory Medicine, Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, Shanxi, China.
Respir Res. 2022 Aug 13;23(1):205. doi: 10.1186/s12931-022-02135-1.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants that may cause long-term lung dysfunction. Accumulating evidence supports the vascular hypothesis of BPD, in which lung endothelial cell dysfunction drives this disease. We recently reported that endothelial carnitine palmitoyltransferase 1a (Cpt1a) is reduced by hyperoxia, and that endothelial cell-specific Cpt1a knockout mice are more susceptible to developing hyperoxia-induced injury than wild type mice. Whether Cpt1a upregulation attenuates hyperoxia-induced endothelial cell dysfunction and lung injury remains unknown. We hypothesized that upregulation of Cpt1a by baicalin or L-carnitine ameliorates hyperoxia-induced endothelial cell dysfunction and persistent lung injury.
Lung endothelial cells or newborn mice (< 12 h old) were treated with baicalin or L-carnitine after hyperoxia (50% and 95% O) followed by air recovery.
We found that incubation with L-carnitine (40 and 80 mg/L) and baicalin (22.5 and 45 mg/L) reduced hyperoxia-induced apoptosis, impaired cell migration and angiogenesis in cultured lung endothelial cells. This was associated with increased Cpt1a gene expression. In mice, neonatal hyperoxia caused persistent alveolar and vascular simplification in a concentration-dependent manner. Treatment with L-carnitine (150 and 300 mg/kg) and baicalin (50 and 100 mg/kg) attenuated neonatal hyperoxia-induced alveolar and vascular simplification in adult mice. These effects were diminished in endothelial cell-specific Cpt1a knockout mice.
Upregulating Cpt1a by baicalin or L-carnitine ameliorates hyperoxia-induced lung endothelial cell dysfunction, and persistent alveolar and vascular simplification. These findings provide potential therapeutic avenues for using L-carnitine and baicalin as Cpt1a upregulators to prevent persistent lung injury in premature infants with BPD.
支气管肺发育不良（BPD）是一种早产儿的慢性肺部疾病，可能导致长期的肺部功能障碍。越来越多的证据支持 BPD 的血管假说，即肺内皮细胞功能障碍驱动这种疾病。我们最近报道，内皮肉碱棕榈酰转移酶 1a（Cpt1a）在高氧环境下减少，内皮细胞特异性 Cpt1a 敲除小鼠比野生型小鼠更容易发生高氧诱导的损伤。Cpt1a 的上调是否能减轻高氧诱导的内皮细胞功能障碍和肺损伤尚不清楚。我们假设，黄芩苷或左旋肉碱上调 Cpt1a 可以改善高氧诱导的内皮细胞功能障碍和持续性肺损伤。
高氧（50%和 95% O2）后，用黄芩苷或左旋肉碱处理肺内皮细胞或新生小鼠（<12 小时），然后恢复空气。
我们发现，用左旋肉碱（40 和 80mg/L）和黄芩苷（22.5 和 45mg/L）孵育可减少高氧诱导的细胞凋亡，损害培养的肺内皮细胞的迁移和血管生成。这与 Cpt1a 基因表达的增加有关。在小鼠中，新生期高氧以浓度依赖的方式导致持续性肺泡和血管简化。用左旋肉碱（150 和 300mg/kg）和黄芩苷（50 和 100mg/kg）治疗可减轻成年小鼠新生期高氧诱导的肺泡和血管简化。这些作用在内皮细胞特异性 Cpt1a 敲除小鼠中减弱。
用黄芩苷或左旋肉碱上调 Cpt1a 可改善高氧诱导的肺内皮细胞功能障碍和持续性肺泡和血管简化。这些发现为使用左旋肉碱和黄芩苷作为 Cpt1a 上调剂，预防早产儿 BPD 持续性肺损伤提供了潜在的治疗途径。
