Hyaluronan and its Receptors in BPD

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）和肺胶原蛋白SP-A和SP-D在狒狒早产和通气模型中的炎症和支气管肺发育不良（BPD）中的作用。来自我们实验室的数据，使用博来霉素诱导的肺损伤的啮齿动物模型，表明肺HA增加与巨噬细胞积聚相关。向博来霉素损伤的动物施用HA结合肽减少炎症和纤维化。此外，我们还发现气管吸出物HA浓度的增加与炎症相关，并可预测患有肺部疾病的早产儿的死亡或BPD。氧化应激和硝化应激是肺损伤和炎症的关键介质。蛋白质构成活性氧（ROS）和氮物质（RNS）的反应性的主要靶标，形成不同的蛋白质加合物，例如3-硝基酪氨酸修饰的表面活性剂蛋白，特别是SP-A和SP-D。此外，ROS和RNS已显示将HA片段化为促进巨噬细胞活化、细胞因子基因表达和趋化性的较低分子量（LMW）形式。初步数据表明，3-硝基酪氨酸在博来霉素损伤的啮齿动物肺和BPD婴儿肺中的差异定位和表达。BPD合作研究计划提供了一个独特的机会来测试HA和肺聚集素对BPD发展的机制贡献。使用狒狒模型的BPD，我们将测试的假设，即浓度升高的低分子量HA和翻译后修饰的肺聚集素，发生的氧化，硝化和亚硝化应激与早产和通气，是不可或缺的，并促进炎症过程之前的发展BPD。限制LMW HA和修饰的凝集素的产生或作用的治疗将限制BPD的发生率和/或严重程度。目的1将在狒狒模型中表征与炎症和氧化、硝化和亚硝基化标志物相关的HA及其受体的发育和出生后表达。目的二是确定狒狒模型中SP-A和SP-D表面活性剂的组成、含量和功能，以及SP-A和SP-D在氧化、硝化和亚硝基化过程中的变化。目的3将研究潜在的治疗方法，包括SOD模拟物，吸入NO和HA结合肽对狒狒BPD模型中炎症，HA和表面活性物质变化的影响。本提案中描述的实验将确定LMW HA和肺凝集素对这些模型结果的贡献，并且是进一步开发基于HA的新型治疗剂以限制人类BPD发生率和/或严重程度的先决条件。

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.