CPAP Drives Lung Growth and Pulmonary Function in Moderately Preterm Primates

 描述(由申请人提供)： 妊娠不到37周的早产是肺部发育异常的最常见原因，并可能导致终身后遗症，因为早产会限制肺发挥其最大潜力的能力。极早产儿(孕24-28周)经常发生支气管肺发育不良(BPD)，他们的生存已将重点从中晚期早产儿(孕30周至孕37周)转移，这些婴儿最初需要的呼吸支持相对较少，很少发生BPD。然而，与足月妊娠分娩的婴儿相比，MLP婴儿是早产儿中的大多数，他们发生喘息性呼吸系统疾病、住院和使用哮喘药物的发生率较高。因此，MLP婴儿在NICU出院后造成高发病率、家庭压力和医疗费用。MLP婴儿的肺功能测试显示，与年龄匹配的足月儿相比，他们的呼气流量减少，在以后的生活中测试时没有表现出追赶。持续气道正压(CPAP)提供机械肺扩张，是NICU维持功能残气量(FRC)、避免插管和气压创伤、减少呼吸道并发症的标准护理。虽然CPAP目前被用于最大限度地减少肺损伤，但它也可能促进肺的生长和发育，因为机械拉伸肺是促进肺生长的重要刺激因素。支持这一点的是，在雪貂的研究中，我们已经证明了1周的CPAP增加了肺容量和气道大小。此外，我们还证明，对成人哮喘患者进行为期一周的夜间CPAP治疗可以抑制呼吸道高反应性，这是一种经常出现在早产儿身上的呼吸道特征。最后，我们发现，在早产儿(平均怀孕32周)和没有发生BPD的婴儿中，在NICU接受CPAP治疗的婴儿比没有接受CPAP治疗的婴儿有更大的肺体积和更大的肺弥散能力。因此，我们假设CPAP可以刺激早产儿的肺生长，改善肺功能，抑制呼吸道高反应性。我们建议在一个高度可翻译的非人类灵长类动物模型中验证这一假设，在该模型中，中度早产(怀孕140天，=165天足月妊娠的85%)恒河猴将接受10天CPAP(5 CmH2O)或假CPAP(0 CmH2O)治疗。在CPAP后10天和6个月龄时进行肺功能和肺结构检查。此外，我们将通过检查机械敏感通路以及确定是否存在可能导致早产对肺功能的终生影响的表观遗传修饰来确定CPAP作用的潜在机制。这项拟议研究的结果可以直接支持临床试验，将CPAP的应用从NICU的呼吸支持改为治疗性干预，以防止肺发育改变，即使是在分娩后没有临床呼吸窘迫症状的中晚期早产儿。

 DESCRIPTION (provided by applicant): Preterm delivery at less than 37 weeks of gestation is the most common cause of abnormal lung development and one with potential lifelong sequelae since preterm delivery can limit the ability of the lung to reach its maximum potential. The survival of extremely premature infants (24-28 wks gestation), who frequently develop bronchopulmonary dysplasia (BPD), has shifted focus away from moderate and late premature (MLP) infants (> 30 to < 37 wks gestation), who initially require relatively little respiratory support and rarely develop BPD. However, MLP infants are the majority of premature births and develop a high incidence of wheezy respiratory illnesses, hospitalizations, and use of asthma medications compared to infants delivered at term gestation. Therefore, MLP infants contribute to high morbidity, family stress, and health care costs following NICU discharge. Pulmonary function testing of MLP infants show they exhibit reduced expiratory flows compared to age-matched term infants and do not demonstrate catch-up when tested in later life. Continuous positive airway pressure (CPAP), which provides mechanical lung distention, is a standard of NICU care for maintaining functional residual capacity (FRC), avoiding intubation and barotrauma, and decreasing respiratory morbidity. While CPAP is currently used to minimize lung injury, it may also promote lung growth and development, since mechanical stretch of the lung is an important stimulus to lung growth. Supporting this, in studies in ferrets, we have demonstrated that 1-week of CPAP increased lung volume and airway size. In addition, we demonstrated that treatment of adult asthmatics with nocturnal CPAP for 1-week suppressed airway hyper-reactivity, an airway characteristic that is often present in subjects born prematurely. Lastly, we have found that among infants born prematurely (mean 32 weeks gestation) and who didn't develop BPD, those treated with CPAP in the NICU had larger lung volumes and greater pulmonary diffusion capacity compared to non-CPAP treated infants. We therefore hypothesize that CPAP stimulates lung growth, improves lung function, and suppresses airway hyper-reactivity in premature infants. We propose to test this hypothesis in a highly-translatable, non-human primate model in which moderately premature (140 days gestation, = 85% of 165 days term gestation) rhesus monkeys will be treated with 10 days CPAP (5 cmH2O) or sham CPAP (0 cmH2O). Pulmonary function and structure will be examined after the 10 days of CPAP and at 6 months of age. In addition we will determine underlying mechanism of CPAP action by examining mechano-sensitive pathways as well as determining if there are epigenetic modifications that may underlie the life-long effects of pre-term birth on lung function. Findings from this proposed study could directly support clinical trials to change the application of CPAP from that of respiratory support in the NICU to that of a therapeutic intervention to prevent altered lung development even in infants delivered as moderate or late preterm without clinical signs of respiratory distress after delivery