Hyaluronan and its Receptors in BPD

BPD 中的透明质酸及其受体

• 批准号: 6947822
• 负责人: RASHMIN C SAVANI
• 金额: $ 29.68万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-03-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947822
• 关键词: antigen presentation; antioxidants; baboons; bombesin; bombesin like peptide; bronchopulmonary dysplasia; carbohydrate receptor; cooperative study; developmental immunology; dosage; electrophoresis; enzyme linked immunosorbent assay; high performance liquid chromatography; hyaluronate; immunity; immunocytochemistry; inflammation; lung development; lung injury; monoclonal antibody; mucopolysaccharides; neuroendocrine system; oxidation; premature infant animal; pulmonary surfactants; respiratory pharmacology

DESCRIPTION (provided by applicant): This proposal focuses on the role of the glycosaminoglycan hyaluronan (hyaluronic acid, HA) and the pulmonary collectins SP-A and SP-D in inflammation and Bronchopulmonary Dysplasia (BPD) in baboon models of preterm birth and ventilation. Data from our laboratory, using the rodent model of bleomycin-induced lung injury, indicates increased lung HA in association with macrophage accumulation. Administration of HA-binding peptide to bleomycin-injured animals decreases inflammation and fibrosis. In addition, we have found increases in tracheal aspirate HA concentrations that correlate with inflammation and are predictive of death or BPD in human preterm infants with lung disease. Oxidative and nitrative stresses are critical mediators of lung injury and inflammation. Proteins constitute a major target of reactivity for reactive oxygen (ROS) and nitrogen species (RNS) forming distinct protein adducts such as 3-nitrotyrosine-modified surfactant proteins, in particular SP-A and SP-D. Further, ROS and RNS have been shown to fragment HA into lower molecular weight (LMW) forms that promote macrophage activation, cytokine gene expression and chemotaxis. Preliminary data indicate differential localization and expression of 3-nitrotyrosine in rodent lungs injured with bleomycin and infant lungs with BPD. The Program for Collaborative Research on BPD provides a unique opportunity to test the mechanistic contribution of HA and pulmonary collectins to the development of BPD. Using the baboon models of BPD, we will test the hypothesis that elevated concentrations of LMW HA and post-translational modification of pulmonary collectins, occurring as a result of oxidative, nitrative and nitrosative stresses associated with preterm birth and ventilation, are integral to and promote the inflammatory process that precedes the development of BPD. Therapies that limit the production or effects of LMW HA and modified collectins will limit the incidence and/or severity of BPD. Aim 1 will characterize the developmental and postnatal expression of HA and its receptors in relation to inflammation and markers of oxidation, nitration and nitrosylation in the baboon models. Aim 2 will focus on determining surfactant composition, content and function, as well as the changes in oxidation, nitration and nitrosylation of SP-A and SP-D in the baboon models. Aim 3 will examine the effects of potential therapies, including SOD mimetics, inhaled NO and HA-binding peptides on the inflammatory, HA and surfactant changes in the baboon BPD models. The experiments described in this proposal will define the contribution of LMW HA and pulmonary collectins to the outcomes of these models and are a pre-requisite to further development of novel HA-based therapeutics to limit the incidence and/or severity of BPD in humans.

描述（由申请人提供）： 该提案的重点是糖胺聚糖透明质酸（透明质酸，HA）和肺collectins sp-a和sp-d在炎症和支气管肺发育不良（BPD）中的作用。使用博来霉素诱导的肺损伤的啮齿动物模型，我们实验室的数据表明，与巨噬细胞积累相关的肺HA增加。给予HA结合肽对博来霉素受伤的动物的施用可减少炎症和纤维化。此外，我们发现气管抽吸HA浓度增加，与炎症相关，并预测患有肺部疾病的人类早产儿的死亡或BPD。氧化和硝化应力是肺损伤和炎症的关键介质。蛋白质构成了反应性氧（ROS）和氮种（RNS）的反应性主要靶标，该蛋白质形成不同的蛋白质加合物，例如3-硝基酪氨酸改性的表面活性剂蛋白，尤其是SP-A和SP-D。此外，ROS和RN已显示出片段成分为较低的分子量（LMW）形式，这些形式促进巨噬细胞激活，细胞因子基因表达和趋化性。初步数据表明，三硝基酪氨酸在啮齿动物肺中的差异性定位和表达，患有博来霉素和婴儿肺的啮齿动物肺和BPD的婴儿。关于BPD的合作研究计划提供了一个独特的机会，可以测试HA和肺collectins对BPD发展的机械贡献。使用BPD的狒狒模型，我们将测试以下假设：肺集合蛋白的LMW HA浓度升高，而肺收集蛋白的翻译后修饰，这是由于氧化，硝酸和硝化应力而导致的，与早产和频静脉相关，是对BPD发展的炎症过程的积分，并促进了炎症过程。限制LMW HA和经过修改的集群蛋白的产生或影响的疗法将限制BPD的发病率和/或严重程度。 AIM 1将表征HA及其受体的发育和产后表达与狒狒模型中氧化，硝化和硝基化的标志有关。 AIM 2将集中于确定表面活性剂组成，含量和功能，以及狒狒模型中SP-A和SP-D的氧化，硝化和硝基化的变化。 AIM 3将检查潜在疗法的影响，包括SOD模拟物，吸入NO和HA结合肽对狒狒BPD模型中炎症，HA和表面活性剂变化的影响。本提案中描述的实验将定义LMW HA和肺集合蛋白对这些模型结果的贡献，并且是进一步发展基于HA的新型治疗剂以限制人类BPD的发病率和/或人类严重程度的前提。