Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury

被引:98
作者
de Visser, Yvonne P. [1 ]
Walther, Frans J. [1 ,3 ]
Laghmani, El Houari [1 ]
Boersma, Hester [1 ]
Van der Laarse, Arnoud [2 ]
Wagenaar, Gerry T. M. [1 ]
机构
[1] Leiden Univ, Med Ctr, Dept Pediat, Div Neonatol, NL-2300 RC Leiden, Netherlands
[2] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands
[3] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat, Torrance, CA 90502 USA
基金
美国国家卫生研究院;
关键词
ENDOTHELIAL GROWTH-FACTOR; INHALED NITRIC-OXIDE; PHOSPHODIESTERASE-5; INHIBITOR; NATRIURETIC PEPTIDES; CARDIAC MYOCYTES; ORAL SILDENAFIL; TENASCIN-C; HYPERTENSION; INFANTS; NEWBORN;
D O I
10.1186/1465-9921-10-30
中图分类号
R56 [呼吸系及胸部疾病];
学科分类号
摘要
Background: 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. Methods: 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. Results: 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). Conclusion: 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.
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页数:16
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