西地那非治疗支气管肺发育不良

    支气管肺发育不良(Bronchopulmonary dysplasia ，BPD)是早产儿少见的慢性肺疾病，特征为肺泡结构停止生长发育/肺泡结构缺失，其发病机制尚不清楚，现在认为可能是肺发育过程中血管内皮生长因子信号受损和一氧化氮生成减少，从而导致肺发育期间肺泡和肺血管的发育障碍。一氧化氮依靠刺激cGMP生成而发挥作用。由于磷酸二酯酶使cGMP失去活性，因此，特异性磷酸二酯酶抑制剂西地那非可能有促进新生鼠肺血管生成和减轻氧诱导的肺损害作用。在体外研究发现，西地那非增加人肺内皮细胞暴露与高氧环境中的血管网形成。动物实验证明，足月新生鼠暴露与高氧后肺泡数量减少、肺泡扩大、毛细血管密度降低，与模拟人支气管肺发育不良的病理特征相似。这些结构异常可导致肺发育迟缓、右心室肥大和废血管壁增厚。西地那非促进肺泡生成、降低肺血管阻力、右心室肥大和血管壁肥厚。

    作者认为，NO/cGMP通路在肺泡发育时期起重要作用。西地那非可用语治疗肺泡结构损害相关的疾病。

Sildenafil Improves Alveolar Growth and Pulmonary Hypertension in Hyperoxia-induced Lung Injury

Faruqa Ladha,Sebastien Bonnet,Farah Eaton,Kyoko.Am J RES Crit Care Med,2007-5-4.

ABSTRACT Rationale: Bronchopulmonary dysplasia (BPD), the chronic lung disease of preterm infants, and pulmonary emphysema, both significant global health problems, are characterized by an arrest in alveolar growth/loss of alveoli structures. Mechanisms that inhibit distal lung growth are poorly understood, but recent studies suggest that impaired vascular endothelial growth factor signaling and reduced nitric oxide (NO) production decreases alveolar and vessel growth in the developing lung, features observed in experimental oxygen-induced BPD. NO exerts its biological activity by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production. Objectives: Because cGMP is inactivated by phosphodiesterase (PDE) enzymes, we hypothesized that the cGMP-specific PDE5 inhibitor sildenafil would promote angiogenesis and attenuate oxygen-induced lung injury in newborn rats. Methods, Measurements, and Main Results: In vitro, sildenafil (10eC4 M) increased endothelial capillary network formation of human pulmonary endothelial cells exposed to hyperoxia. In vivo, rat pups were randomly exposed from birth to normoxia, hyperoxia (95% O2, BPD model), and hyperoxia+sildenafil (100 mg/kg/day subcutaneously). Rat pups exposed to hyperoxia showed fewer and enlarged air spaces as well as decreased capillary density, mimicking pathologic features seen in human BPD. These structural anomalies were associated with echographic (decreased pulmonary acceleration time) and structural (right ventricular hypertrophy and increased medial wall thickness) signs of pulmonary hypertension. Sildenafil preserved alveolar growth and lung angiogenesis, and decreased pulmonary vascular resistance, right ventricular hypertrophy and medial wall thickness. Conclusions: Our findings suggest a role for the NO/cGMP pathway during alveolar development. Sildenafil may have therapeutic potential in diseases associated with impaired alveolar structures.