Hyaluronan and its Receptors in BPD

描述(由申请人提供)： 本研究的重点是糖胺聚糖透明质酸(HA)和肺集合素SP-A和SP-D在早产和呼吸机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。来自我们实验室的数据，使用博莱霉素诱导的肺损伤的啮齿动物模型，表明肺透明质酸增加与巨噬细胞聚集有关。给博莱霉素损伤的动物注射HA结合肽可以减少炎症和纤维化。此外，我们还发现，在患有肺部疾病的早产儿中，气管吸入物HA浓度的增加与炎症相关，并可预测死亡或BPD。氧化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)和氮物种(RNS)形成不同的蛋白质加合物的主要目标，例如3-硝基酪氨酸修饰的表面活性蛋白质，特别是SP-A和SP-D。此外，ROS和RNS已被证明能将HA片断成低分子(LMW)形式，促进巨噬细胞激活、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大鼠肺和BPD的婴儿肺中的定位和表达存在差异。BPD合作研究计划提供了一个独特的机会来测试HA和肺集合素在BPD发展中的作用机制。使用BPD的狒狒模型，我们将检验这样的假设，即BPD发展之前的炎症过程中，低分子HA浓度升高和肺集合素翻译后修饰是早产和呼吸相关的氧化、硝化和亚硝化应激的结果，是BPD发生之前的炎症过程的组成部分和促进。限制低分子HA和修饰的胶原素的产生或效果的治疗将限制BPD的发生率和/或严重程度。目的1研究在恒河猴模型中HA及其受体在发育和出生后的表达与炎症以及氧化、硝化和亚硝化标志的关系。目的2将重点测定表面活性物质的组成、含量和功能，以及在恒河猴模型中SP-A和SP-D的氧化、硝化和亚硝化的变化。目的3将研究潜在的治疗方法，包括SOD模拟物、吸入NO和HA结合肽对恒河猴BPD模型炎症、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低分子HA和肺集合素对这些模型结果的贡献，并是进一步开发基于HA的新疗法以限制BPD在人类中的发病率和/或严重性的先决条件。

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.