Nitric oxide effects on bronchopulmonary dysplasia

(申请人摘要)支气管肺发育不良(BPD)常合并 早产后延长机械通气时间。定义 引起BPD的机制和开发安全、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 为了测试各种治疗措施，我们培育了一只早产羔羊 模拟这种疾病的临床和病理结果的模型。这个 潜在的假设是未成熟的婴儿出生后早期发炎 肺暴露在富含02气体的长时间重复拉伸中会导致 氧化剂和蛋白水解酶可抑制或预防的肺损伤 早期和持续的出生后吸入一氧化氮(INO)， 对此的反应可以通过产前类固醇治疗来增强。这项建议 有三个具体目标：(I)比较出生后即刻和延迟(7d) 连续、低剂量注射iNO(和相应的对照，NO iNO) (Ii)确定产前是否使用类固醇。 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 肺循环和呼吸道的出生后适应， 从而改善了呼吸气体交换。该项目是对 静脉注射一氧化氮治疗早产儿呼吸衰竭的临床研究连载 支气管分泌物，肺灌洗液和肺淋巴的样本 进展性BPD的炎症评估。研究计划包括 生理、生化、组织学和分子技术以确定 肺循环异常的潜在机制(持续性 血管阻力升高，因血管滤过增加而引起的浮肿 压力，对iNO的肺血管扩张剂反应丧失，增加 动脉平滑肌，微血管数量减少，毛细血管减少 表面密度、内皮型一氧化氮合酶和血管内皮细胞一氧化氮合酶表达降低 可溶性鸟苷环化酶)；呼吸道(呼气增加 阻力、细支气管壁平滑肌增殖、数量减少 肺泡)和肺间质(肺弹性蛋白原表达增加和 弹性蛋白紊乱堆积)，这是BPD羔羊模型的特征。 与SCOR其他侧重于表面活性剂的项目合作研究 蛋白质与功能(I)、血管内皮生长因子及其 受体(II)、炎性介质(III)和有丝分裂原对血管平滑肌的影响 肌肉增殖和结缔组织元素(IV)将提供新的 BPD肺功能障碍和异型增生的发病机制及其影响 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.