HYALURONAN AND ITS RECEPTORS IN BPD

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究的重点是糖胺聚糖透明质酸（透明质酸，HA）和肺集合物SP-A和SP-D在早产和通气的狒狒模型中的炎症和支气管肺发育不良（BPD）中的作用。我们实验室使用博莱霉素诱导的啮齿动物肺损伤模型的数据表明，肺HA增加与巨噬细胞积聚有关。给博莱霉素损伤的动物注射ha结合肽可减少炎症和纤维化。此外，我们发现气管吸入血凝素浓度的增加与炎症有关，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重要介质。蛋白质是活性氧（ROS）和氮物质（RNS）形成不同蛋白质加合物的主要目标，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已被证明可将HA裂解为低分子量（LMW）形式，从而促进巨噬细胞活化、细胞因子基因表达和趋化。初步数据表明，3-硝基酪氨酸在博莱霉素损伤的啮齿动物肺和BPD患儿肺中的定位和表达存在差异。BPD合作研究项目提供了一个独特的机会来测试血凝素和肺收集物对BPD发展的机制贡献。使用BPD的狒狒模型，我们将验证LMW HA浓度升高和肺集合翻译后修饰的假设，这是与早产和通气相关的氧化、硝化和亚硝化应激的结果，是BPD发展之前炎症过程的组成部分并促进了炎症过程。限制LMW HA和修饰集合的产生或作用的治疗将限制BPD的发病率和/或严重程度。目的1将描述狒狒模型中HA及其受体与炎症和氧化、硝化和亚硝基化标志物相关的发育和出生后表达。目的2将重点研究表面活性剂的组成、含量和功能，以及SP-A和SP-D在狒狒模型中的氧化、硝化和亚硝基化变化。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和表面活性剂变化的影响。本提案中描述的实验将确定LMW HA和肺集合对这些模型结果的贡献，并且是进一步开发基于HA的新型治疗方法以限制人类BPD发病率和/或严重程度的先决条件。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 an 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.