Rationale: Apelin, a potent vasodilator and angiogenic factor, may be a novel therapeutic agent in neonatal chronic lung disease, including bronchopulmonary dysplasia.Objectives: To determine the beneficial effect of apelin in neonatal rats with hyperoxia-induced lung injury, a model for premature infants with bronchopulmonary dysplasia.Methods: The cardiopulmonary effects of apelin treatment (62 μg/kg/d) were studied in neonatal rats by exposure to 100% oxygen, using two treatment strategies: early concurrent treatment during continuous exposure to hyperoxia for 10 days and late treatment and recovery in which treatment was started on Day 6 after hyperoxic injury for 9 days and continued during the 9-day recovery period. We investigated in both models the role of the nitric oxide–cyclic guanosine monophosphate (cGMP) pathway in apelin treatment by specific inhibition of the nitric oxide synthase activity with Nω-nitro-l-arginine methyl ester (l-NAME, 25 mg/kg/d).Measurements and Main Results: Parameters investigated include survival, lung and heart histopathology, pulmonary fibrin deposition and inflammation, alveolar vascular leakage, lung cGMP levels, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue. Prophylactic treatment with apelin improved alveolarization and angiogenesis, increased lung cGMP levels, and reduced pulmonary fibrin deposition, inflammation, septum thickness, arteriolar wall thickness, and right ventricular hypertrophy. These beneficial effects were completely absent in the presence of l-NAME. In the injury-recovery model apelin also improved alveolarization and angiogenesis, reduced arteriolar wall thickness, and attenuated right ventricular hypertrophy.Conclusions: Apelin reduces pulmonary inflammation, fibrin deposition, and right ventricular hypertrophy, and partially restores alveolarization in rat pups with neonatal hyperoxic lung injury via a nitric oxide synthase–dependent mechanism.
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机译：理由：Apelin是有效的血管扩张剂和血管生成因子，可能是新生儿慢性肺部疾病（包括支气管肺发育不良）的新型治疗剂。目的：确定apelin在高氧血症引起的肺损伤新生大鼠的有益作用方法：采用两种治疗策略，通过暴露于100％氧气的新生大鼠研究apelin治疗（62μg/ kg / d）对心肺功能的影响：两种方法：在持续暴露于高氧持续10天期间的早期同时治疗;以及晚期治疗和恢复，其中高氧损伤后第6天开始治疗9天，并在9天恢复期内继续治疗。我们在这两个模型中均通过特异性抑制Nω-硝基-1-精氨酸甲酯的一氧化氮合酶活性，研究了一氧化氮-环鸟苷一磷酸（cGMP）途径在apelin治疗中的作用（l-NAME，25 mg / kg / d）。测量和主要结果：研究的参数包括生存率，肺和心脏组织病理学，肺纤维蛋白沉积和炎症，肺泡血管渗漏，肺cGMP水平，右心室肥大以及肺和心脏组织中差异mRNA表达。用apelin进行预防性治疗可改善肺泡形成和血管生成，增加肺cGMP水平，并减少肺纤维蛋白沉积，炎症，隔膜厚度，小动脉壁厚度和右心室肥大。在存在l-NAME的情况下，完全没有这些有益效果。在损伤恢复模型中，Apelin还改善了肺泡形成和血管生成，降低了小动脉壁厚度并减轻了右心室肥大。一氧化氮合酶依赖性机制造成的损伤。
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