Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury
Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury
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DOI：
10.1152/ajplung.00360.2012
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发表时间：
2013-09-01
影响因子：
4.9
通讯作者：
Walther, Frans J.
中科院分区：
文献类型：
--
作者：
Wagenaar, Gerry T. M.;Laghmani, El Houari;Walther, Frans J.
MAS癌基因受体（MAS）或血管紧张素（Ang）受体2型（AT 2）的刺激可能是新生儿慢性肺疾病（CLD）的新的治疗选择，通过抵消强效血管收缩剂血管紧张素II的不良反应，包括动脉高压（PAH）诱导的右心室肥大（RVH）和肺部炎症。我们测定了CLD新生大鼠在连续暴露于100%氧气中10天期间每天用MAS [cyclic Ang-（1-7）; 10-50 μ g.kg（-1）.day（-1）]和AT 2 [dKcAng-（1-7）; 5-20 μ g.kg（-1）.day（-1）]的特异性配体治疗的心肺效应。研究的参数包括肺和心脏组织病理学、纤维蛋白沉积、血管渗漏和参与肾素-血管紧张素系统、炎症、凝血和肺泡发育的关键基因在肺中的差异mRNA表达。我们研究了在AT 2激动剂治疗期间用N-ω-硝基-L-精氨酸甲酯（25 mg.kg（-1）.day（-1））抑制一氧化氮合酶的作用。用MAS或AT 2激动剂预防性治疗10天，通过减少肺泡间隔厚度和小动脉中壁厚度以及防止RVH来减少心肺损伤。两种激动剂均减弱了炎性细胞（包括巨噬细胞（通过AT 2）和中性粒细胞（通过MAS））的肺内流，但未减少肺泡扩大和血管肺泡渗漏。AT 2激动剂减弱高氧诱导的纤维蛋白沉积。总之，MAS或AT 2的刺激通过减少肺部炎症和预防PAH诱导的RVH来减轻心肺损伤，但不影响实验性CLD新生大鼠的肺泡和血管发育。AT 2激活对实验性CLD的有益作用是通过NOS非依赖性机制介导的。
Stimulation of MAS oncogene receptor (MAS) or angiotensin (Ang) receptor type 2 (AT2) may be novel therapeutic options for neonatal chronic lung disease (CLD) by counterbalancing the adverse effects of the potent vasoconstrictor angiotensin II, consisting of arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH) and pulmonary inflammation. We determined the cardiopulmonary effects in neonatal rats with CLD of daily treatment during continuous exposure to 100% oxygen for 10 days with specific ligands for MAS [cyclic Ang-(1-7); 10-50 mu g.kg(-1).day(-1)] and AT2 [dKcAng-(1-7); 5-20 mu g.kg(-1).day(-1)]. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in the renin-angiotensin system, inflammation, coagulation, and alveolar development. We investigated the role of nitric oxide synthase inhibition with N-omega-nitro-L-arginine methyl ester (25 mg.kg(-1).day(-1)) during AT2 agonist treatment. Prophylactic treatment with agonists for MAS or AT2 for 10 days diminished cardiopulmonary injury by reducing alveolar septum thickness and medial wall thickness of small arterioles and preventing RVH. Both agonists attenuated the pulmonary influx of inflammatory cells, including macrophages (via AT2) and neutrophils (via MAS) but did not reduce alveolar enlargement and vascular alveolar leakage. The AT2 agonist attenuated hyperoxia-induced fibrin deposition. In conclusion, stimulation of MAS or AT2 attenuates cardiopulmonary injury by reducing pulmonary inflammation and preventing PAH-induced RVH but does not affect alveolar and vascular development in neonatal rats with experimental CLD. The beneficial effects of AT2 activation on experimental CLD were mediated via a NOS-independent mechanism.