Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats.
Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats.
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DOI：
10.1111/apha.12622
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Wagenaar GT
中科院分区：
文献类型：
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作者：
Chen X;Walther FJ;van Boxtel R;Laghmani EH;Sengers RM;Folkerts G;DeRuiter MC;Cuppen E;Wagenaar GT
通过阻断溶血磷脂酸（LPA）受体（LPAR） 1可能是支气管肺发育不良（BPD）的一种新的治疗选择，它可以防止lpar1介导的配体（LPA）的不良反应，包括肺部炎症、肺动脉高压（PAH）和纤维化。在Wistar实验性BPD大鼠中，连续暴露于100%氧气10天，我们确定了LPAR1缺乏对LPAR1细胞质螺旋8错意突变和LPAR1和-3被Ki16425阻断的新生大鼠的有益作用。研究参数包括存活、肺和心脏组织病理学、纤维蛋白和胶原沉积、血管渗漏、肺中参与LPA信号传导和BPD发病的关键基因mRNA的差异表达。LPAR1突变大鼠通过肺泡间隔厚度减少、肺部炎症（巨噬细胞和中性粒细胞内流减少、CINC1表达减少）和III型胶原沉积来预防实验性BPD和死亡率。然而，LPAR1突变大鼠对肺泡增大、小动脉内侧壁厚度增加、纤维蛋白沉积和血管肺泡渗漏没有保护作用。用Ki16425治疗实验性BPD证实了在LPAR1突变大鼠中观察到的数据，但并没有降低实验性BPD大鼠肺中性粒细胞内流、CINC1表达和死亡率。此外，Ki16425治疗对PAH和右心室肥厚有保护作用。LPAR1缺乏通过减少肺部炎症和纤维化来减轻肺损伤，从而降低死亡率，但不影响肺泡和血管发育，并且与Ki16425治疗不同，不能预防实验性BPD新生大鼠的PAH。
Blocking of lysophosphatidic acid (LPA) receptor (LPAR) 1 may be a novel therapeutic option for bronchopulmonary dysplasia (BPD) by preventing the LPAR1-mediated adverse effects of its ligand (LPA), consisting of lung inflammation, pulmonary arterial hypertension (PAH) and fibrosis. In Wistar rats with experimental BPD, induced by continuous exposure to 100% oxygen for 10 days, we determined the beneficial effects of LPAR1 deficiency in neonatal rats with a missense mutation in cytoplasmic helix 8 of LPAR1 and of LPAR1 and -3 blocking with Ki16425. Parameters investigated included survival, lung and heart histopathology, fibrin and collagen deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in LPA signalling and BPD pathogenesis. LPAR1 mutant rats were protected against experimental BPD and mortality with reduced alveolar septal thickness, lung inflammation (reduced influx of macrophages and neutrophils, and CINC1 expression), and collagen III deposition. However, LPAR1 mutant rats were not protected against alveolar enlargement, increased medial wall thickness of small arterioles, fibrin deposition, and vascular alveolar leakage. Treatment of experimental BPD with Ki16425 confirmed the data observed in LPAR1 mutant rats, but did not reduce the pulmonary influx of neutrophils, CINC1 expression, and mortality in rats with experimental BPD. In addition, Ki16425 treatment protected against PAH and right ventricular hypertrophy. LPAR1 deficiency attenuates pulmonary injury by reducing pulmonary inflammation and fibrosis, thereby reducing mortality, but does not affect alveolar and vascular development and, unlike Ki16425 treatment, does not prevent PAH in neonatal rats with experimental BPD.