Nitric oxide effects on bronchopulmonary dysplasia

（申请人的摘要）支气管肺发育不良（BPD）通常使 早产后长时间机械通气。定义 导致BPD的机制，并制定安全，有效的治疗策略 是这个项目的最终目标。探讨BPD的发病机制 为了测试各种治疗干预，我们培育了一只早产羔羊 该模型模拟了该疾病的临床和病理学发现。的 潜在的假设是，出生后早期未成熟的炎症 肺暴露于具有富O2气体的长时间重复拉伸导致 氧化剂和蛋白酶诱导的肺损伤，可通过 出生后早期和持续吸入一氧化氮（iNO）， 产前类固醇治疗可能会增强这种反应。该提案 有3个具体目标：（i）比较出生后即刻与延迟（7天） 连续、低剂量iNO的递送（和相关对照，无iNO）， 长期通气早产羔羊;（ii）以确定是否产前类固醇 治疗将改变对立即或延迟的iNO的反应;和（iii） 确定iNO是否会抑制肺部炎症，从而促进 出生后肺循环和呼吸道的适应， 导致改善的呼吸气体交换。该项目补充了 iNO治疗早产儿呼吸衰竭的临床试验串行 支气管分泌物、肺灌洗液和肺淋巴液的样本将允许 评估BPD进展中的炎症。研究计划包括 生理学、生物化学、组织学和分子技术来定义 肺循环异常的潜在机制（持续性 血管阻力升高，血管滤过增加导致水肿 压力，肺血管扩张剂对iNO的反应丧失，增加 动脉平滑肌，微血管数量减少，毛细血管减少 内皮型一氧化氮合酶表达减少， 可溶性鸟苷酸环化酶）;呼吸道（呼气增加 阻力、细支气管平滑肌增生、数量减少 肺泡）;和肺水肿（肺弹性蛋白原表达增加， 无序的弹性蛋白积聚），其表征BPD的Lamb模型。 与其他SCOR项目的合作研究，重点是表面活性剂 蛋白质与功能（一）、血管内皮生长因子及其 受体（II），炎症介质（III），和有丝分裂原，影响平滑 肌肉增殖和结缔组织元素（IV）将提供新的 对BPD肺功能障碍和发育不良机制的认识及其影响 iNO和产前类固醇对这些异常的影响。

(Applicant's Abstract) Bronchopulmonary dysplasia (BPD) often complicates prolonged mechanical ventilation after premature birth. Defining the mechanisms that cause BPD and developing a safe, effective treatment strategy are the ultimate objectives of this project. To study the pathogenesis of BPD and to test various therapeutic interventions, we developed a preterm lamb model that mimics the clinical and pathological findings of this disease. The underlying hypothesis is that early postnatal inflammation of the immature lung exposed to prolonged, repetitive stretch with 02-enriched gas leads to oxidant and protease induced lung injury that can be inhibited or prevented by early and continuous postnatal delivery of inhaled nitric oxide (iNO), the response to which may be enhanced by antenatal steroid treatment. The proposal has 3 specific aims: (i) to compare immediate vs delayed (7d) postnatal delivery of continuous, low-dose iNO (and the relevant control, no iNO) in chronically ventilated preterm lambs; (ii) to determine if antenatal steroid treatment will modify the response to immediate or delayed iNO; and (iii) to determine if iNO will inhibit lung inflammation and thereby facilitate postnatal adaptation of the pulmonary circulation and respiratory tract, leading to improved respiratory gas exchange. This project complements the clinical trial of iNO in preterm infants with respiratory failure. Serial specimens of bronchial secretions, lung lavage fluid and lung lymph will allow assessment of inflammation in evolving BPD. The research plan includes physiological, biochemical, histological and molecular techniques to define mechanisms underlying abnormalities in the lung circulation (persistent elevation of vascular resistance, edema from increased vascular filtration pressure, loss of the pulmonary vasodilator response to iNO, increased arterial smooth muscle, reduced numbers of microvessels and less capillary surface density, decreased expression of endothelial nitric oxide synthase and soluble guanylate cyclase); respiratory tract (increased expiratory resistance, proliferation of bronchiolar smooth muscle, reduced numbers of alveoli); and lung interstitium (increased lung tropoelastin expression and disordered elastin accumulation) that characterize the lamb model of BPD. Collaborative studies with other SCOR projects that focus on surfactant proteins and function (I), vascular endothelial growth factor and its receptors (II), inflammatory mediators (III), and mitogens that influence smooth muscle proliferation and connective tissue elements (IV) will provide new insight on mechanisms of lung dysfunction and dysplasia in BPD and the impact of iNO and antenatal steroids on these abnormalities.