Nitric oxide effects on bronchopulmonary dysplasia

一氧化氮对支气管肺发育不良的影响

• 批准号: 6655317
• 负责人: RICHARD David BLAND
• 金额: $ 26.41万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655317
• 关键词: bronchopulmonary dysplasia; disease /disorder model; embryo /fetus chemotherapy; inflammation; lung development; lung injury; nitric oxide; nonhuman therapy evaluation; pathologic process; premature infant animal; pulmonary circulation; respiratory gas transport; respiratory therapy; sheep; steroids

(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.

（申请人的摘要）支气管肺发育不良（BPD）常常使病情复杂化 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 是该项目的最终目标。研究 BPD 的发病机制 为了测试各种治疗干预措施，我们开发了一只早产羔羊 模拟这种疾病的临床和病理结果的模型。这 潜在的假设是，未成熟婴儿的早期产后炎症 肺暴露于富含 O2 的气体的长时间、重复的拉伸会导致 氧化剂和蛋白酶引起的肺损伤可以通过以下方法抑制或预防 产后早期持续吸入一氧化氮 (iNO) 产前类固醇治疗可能会增强对此的反应。提案 有 3 个具体目标：(i) 比较产后立即与延迟（7 天） 持续输送低剂量 iNO（以及相关对照，无 iNO） 长期通气的早产羔羊； (ii) 确定是否使用产前类固醇 治疗将改变对立即或延迟 iNO 的反应； (iii) 至 确定 iNO 是否会抑制肺部炎症，从而促进 肺循环和呼吸道的产后适应， 从而改善呼吸气体交换。该项目补充了 iNO 治疗呼吸衰竭早产儿的临床试验。串行 支气管分泌物、肺灌洗液和肺淋巴液样本将允许 评估演变中的 BPD 中的炎症。研究计划包括 生理学、生化、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 表面密度、内皮一氧化氮合酶表达降低和 可溶性鸟苷酸环化酶）；呼吸道（呼气增加 抵抗力，细支气管平滑肌增殖，减少数量 肺泡）；和肺间质（肺原弹性蛋白表达增加和 无序的弹性蛋白积累）是 BPD 羔羊模型的特征。 与其他专注于表面活性剂的 SCOR 项目的合作研究 蛋白质与功能（一）、血管内皮生长因子及其 影响平滑肌细胞的受体（II）、炎症介质（III）和有丝分裂原 肌肉增殖和结缔组织成分（IV）将提供新的 深入了解 BPD 中肺功能障碍和发育不良的机制及其影响 iNO 和产前类固醇对这些异常的影响。