Beyond pulmonary hypertension: sildenafil for chronic lung disease of prematurity.
Beyond pulmonary hypertension: sildenafil for chronic lung disease of prematurity.
复制标题
除了肺动脉高压：西地那非治疗早产儿慢性肺病。
DOI：
10.1165/rcmb.2012-0441ed
复制
发表时间：
2013
影响因子：
6.4
通讯作者：
Abman,StevenH
中科院分区：
文献类型：
--
作者：
Steinhorn,RobinH;Kinsella,JohnP;Abman,StevenH
Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy in the United States, and complicates the course of 30% or more of extremely preterm infants (those born before 28 wk gestation). While prenatal steroids and surfactant reduce acute respiratory failure and improve survival, they do not diminish the frequency or severity of BPD (1, 2). Multiple therapies such as hydrocortisone, vitamin A, caffeine, superoxide dismutase, and inhaled nitric oxide have been tested to prevent BPD, but success has been inconsistent and generally modest (3). Extremely preterm infants are born in the late canalicular to early saccular stage of lung development, and must therefore complete a substantial amount of lung development in an extrauterine environment. BPD is often regarded as a form of arrested lung development that occurs when the preterm lung attempts to adapt to air breathing during this developmentally sensitive time period. Fetal lung morphogenesis is a complex process that is orchestrated by multiple transcription factors, growth factors, and environmental influences. The fetus thrives in utero under hypoxic conditions that favor lung growth. In contrast, preterm birth exposes the lung to relative hyperoxia at a critical developmental juncture, which disrupts the normal parenchymal and vascular lung development that is fostered by the presence of hypoxia (4). While supplemental oxygen is frequently required for preterm infants, the preterm lung is poorly equipped to handle it. High levels of inspired oxygen promote oxidative stress in the lung, and are clearly associated with worse pulmonary outcomes (5). On the other hand, a recent clinical trial showed that maintaining oxygen saturation limits at a somewhat lower range (85–89%) reduced the incidence of BPD and retinopathy of prematurity, but increased all-cause mortality by 27%(6). This narrow therapeutic window for oxygen administration further emphasizes the need for lung-targeted therapies that minimize systemic effects.Hypoxia-inducible factors (HIFs) are master regulators of the transcriptional response to hypoxia involved in angiogeneisis, survival, and metabolic pathways. HIFs are constitutively expressed in multiple fetal pulmonary cell types, including epithelial, smooth muscle, and endothelial cells (7). When activated, HIF accumulates in the nucleus and binds to hypoxia response elements of multiple hypoxia-inducible genes including VEGF, SOD2, iNOS, erythropoietin, and others (4, 8). HIF activity is regulated largely at the post-translational level by prolyl hydroxylases (PHDs) that control stability of its a subunit. While HIF-a subunits are rapidly degraded under normoxic conditions, low levels of HIF activation persist and contribute to the basal expression of a large number of genes. Several downstream targets of HIFs likely contribute to abnormal lung development in animal models of BPD and in preterm neonates. One important example is VEGF and VEGF receptor expression, which is decreased in various animal models of BPD induced by hyperoxia or antenatal endotoxin (9–12), as well as in the lungs of premature infants who die with BPD (13, 14). Disruption of pulmonary VEGF leads
