CPAP Drives Lung Growth and Pulmonary Function in Moderately Preterm Primates

 描述（由申请人提供）： 妊娠期小于37周的早产是肺发育异常的最常见原因，并且具有潜在的终身后遗症，因为早产可以限制肺达到其最大潜力的能力。极早产儿（妊娠24-28周）经常发生支气管肺发育不良（BPD），其存活率已从中晚期早产儿（妊娠> 30至< 37周）转移，后者最初需要相对较少的呼吸支持，很少发生BPD。然而，MLP婴儿是大多数早产儿，与足月妊娠分娩的婴儿相比，喘息性呼吸道疾病、住院和使用哮喘药物的发生率较高。因此，MLP婴儿出院后的发病率、家庭压力和医疗保健费用较高。MLP婴儿的肺功能测试显示，与年龄匹配的足月婴儿相比，他们的呼气流量减少，并且在以后的生活中测试时没有表现出追赶。持续气道正压通气（CPAP）提供机械性肺扩张，是NICU护理的标准，用于维持功能性残气量（FRC），避免插管和气压伤，并降低呼吸道发病率。虽然CPAP目前用于最小化肺损伤，但它也可以促进肺生长和发育，因为肺的机械拉伸是肺生长的重要刺激。支持这一点，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，我们还证实了成人哮喘患者夜间CPAP治疗1周可抑制气道高反应性，这是早产儿常见的气道特征。最后，我们发现，在早产儿（平均妊娠32周）和未发生BPD的婴儿中，与非CPAP治疗的婴儿相比，在NICU中接受CPAP治疗的婴儿具有更大的肺体积和更大的肺弥散能力。因此，我们假设CPAP刺激肺生长，改善肺功能，并抑制早产儿气道高反应性。我们建议在高度可翻译的非人灵长类动物模型中检验这一假设，在该模型中，中度早产（妊娠140天，= 165天足月妊娠的85%）恒河猴将接受10天CPAP（5 cmH 2 O）或假CPAP（0 cmH 2 O）治疗。在CPAP治疗10天后和6月龄时检查肺功能和结构。此外，我们将通过检查机械敏感性通路以及确定是否存在可能导致早产对肺功能终身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干预，以防止即使在分娩后没有呼吸窘迫临床体征的中度或晚期早产婴儿中发生肺发育改变

 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