de Visser Yvonne P, Walther Frans J, Laghmani El Houari, Boersma Hester, van der Laarse Arnoud, Wagenaar Gerry Tm
Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
Respir Res. 2009 Apr 29;10(1):30. doi: 10.1186/1465-9921-10-30.
Phosphodiesterase-5 inhibition with sildenafil has been used to treat severe pulmonary hypertension and bronchopulmonary dysplasia (BPD), a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome.
Sildenafil treatment was investigated in 2 models of experimental BPD: a lethal neonatal model, in which rat pups were continuously exposed to hyperoxia and treated daily with sildenafil (50-150 mg/kg body weight/day; injected subcutaneously) and a neonatal lung injury-recovery model in which rat pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room air and started sildenafil treatment on day 6 of hyperoxia exposure. Parameters investigated include survival, histopathology, fibrin deposition, alveolar vascular leakage, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue.
Prophylactic treatment with an optimal dose of sildenafil (2 x 50 mg/kg/day) significantly increased lung cGMP levels, prolonged median survival, reduced fibrin deposition, total protein content in bronchoalveolar lavage fluid, inflammation and septum thickness. Treatment with sildenafil partially corrected the differential mRNA expression of amphiregulin, plasminogen activator inhibitor-1, fibroblast growth factor receptor-4 and vascular endothelial growth factor receptor-2 in the lung and of brain and c-type natriuretic peptides and the natriuretic peptide receptors NPR-A, -B, and -C in the right ventricle. In the lethal and injury-recovery model we demonstrated improved alveolarization and angiogenesis by attenuating mean linear intercept and arteriolar wall thickness and increasing pulmonary blood vessel density, and right ventricular hypertrophy (RVH).
Sildenafil treatment, started simultaneously with exposure to hyperoxia after birth, prolongs survival, increases pulmonary cGMP levels, reduces the pulmonary inflammatory response, fibrin deposition and RVH, and stimulates alveolarization. Initiation of sildenafil treatment after hyperoxic lung injury and continued during room air recovery improves alveolarization and restores pulmonary angiogenesis and RVH in experimental BPD.
西地那非抑制磷酸二酯酶5已被用于治疗重度肺动脉高压和支气管肺发育不良（BPD），这是一种在因呼吸窘迫综合征接受机械通气的极早产儿中发生的慢性肺部疾病。
在两种实验性BPD模型中研究了西地那非治疗：一种是致死性新生儿模型，其中幼鼠持续暴露于高氧环境，并每日用西地那非（50 - 150毫克/千克体重/天；皮下注射）治疗；另一种是新生儿肺损伤 - 恢复模型，其中幼鼠暴露于高氧环境9天，随后在室内空气中恢复9天，并在高氧暴露第6天开始西地那非治疗。研究的参数包括存活率、组织病理学、纤维蛋白沉积、肺泡血管渗漏、右心室肥厚以及肺和心脏组织中的差异mRNA表达。
用最佳剂量的西地那非（2×50毫克/千克/天）进行预防性治疗可显著提高肺cGMP水平、延长中位生存期、减少纤维蛋白沉积、支气管肺泡灌洗液中的总蛋白含量、炎症和隔膜厚度。西地那非治疗部分纠正了肺中双调蛋白、纤溶酶原激活物抑制剂 - 1、成纤维细胞生长因子受体 - 4和血管内皮生长因子受体 - 2以及右心室中脑钠肽和C型钠尿肽以及钠尿肽受体NPR - A、 - B和 - C的差异mRNA表达。在致死性和损伤 - 恢复模型中，我们通过减小平均线性截距和小动脉壁厚度以及增加肺血管密度和右心室肥厚（RVH），证明了肺泡化和血管生成得到改善。
出生后与高氧暴露同时开始的西地那非治疗可延长生存期、提高肺cGMP水平、减少肺部炎症反应、纤维蛋白沉积和RVH，并刺激肺泡化。在高氧性肺损伤后开始并在室内空气恢复期间持续进行的西地那非治疗可改善实验性BPD中的肺泡化，并恢复肺血管生成和RVH。
