Platelet-Derived Growth Factor, Remodeling and Asthma

血小板衍生生长因子、重塑和哮喘

基本信息

批准号：
7858429
负责人：
Monica Kraft
金额：
$ 26.95万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7858429
关键词：
Adjuvant Therapy Adrenal Cortex Hormones Asthma Biopsy Biopsy Specimen Bronchoscopy Characteristics Clinical Collagen Critical Pathways Deposition Distal Elastin Environment Exhibits Fibroblasts Goals Goblet Cells Growth Growth Factor Inhibition Human Hyperplasia Individual Inflammation Interleukin-13 Lead Ligands Link Lung Measures Mediating Mediator of activation protein Pathologic Pathway interactions Pharmaceutical Preparations Physiological Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Process Production Protein Isoforms Proteins Recruitment Activity Research Personnel Resistance Respiratory physiology Smooth Muscle Steroids Testing Therapeutic Agents Time Tissues Work Wound Healing airway inflammation airway obstruction airway remodeling asthmatic airway cell type cytokine improved in vivo muscle hypertrophy novel therapeutics programs receptor response

项目摘要

DESCRIPTION (provided by applicant): Airway remodeling in asthma is a process of permanent structural changes occurring over time, resulting in a component of fixed airway obstruction that can lead to reduced lung function and reduced responsiveness to medications. We have shown that airway inflammation occurs in both the proximal and distal lung in asthma, and we propose that remodeling occurs in both lung compartments. The overall goal of this proposal is to examine critical pathways resulting in dysregulation of airway fibroblast growth and matrix expression throughout the lung that lead to airway remodeling in asthma. A cell type that links inflammation to structural airway changes is the airway fibroblast. Platelet-derived growth factor (PDGF) is a mediator produced by fibroblasts that is induced by IL-13 and is instrumental in tissue repair. In preliminary studies, we demonstrate important differences in primary fibroblasts cultured from the airways of normal and asthmatic subjects. Primary fibroblasts isolated from the asthmatic airways exhibit major disturbances in the critical mitogenic PDGF pathway. We show increased production of PDGF in response to TH2 cytokines, altered expression of PDGF receptor isoforms and changes in matrix expression in response to PDGF. In addition, corticosteroids augment growth in fibroblasts isolated from mild and severe asthmatics as compared to fibroblasts from normal controls; this effect is abrogated when PDGF is inhibited. The hypothesis to be tested is that the TH2 environment induces expression of platelet-derived growth factor (PDGF); PDGF enhances the airway remodeling process in asthma by increasing airway fibroblast growth and collagen expression and by decreasing elastin expression in both the proximal and distal lung. These processes result in a reduction in lung function, airway collapsibility and loss of elastic recoil. Corticosteroids, the mainstay of therapy for asthma, do not suppress but enhance these processes. To test this hypothesis, we will recruit subjects with mild and severe asthma and normal controls who will undergo bronchoscopy with proximal (endobronchial) and distal (transbronchial) lung biopsy. We will determine PDGF expression in the lung, and whether its expression is modulated by IL- 13 (Specific Aim 1). In Specific Aim 2 we will determine that PDGF modulates fibroblast collagen and elastin expression throughout the lung, and that this modulation predicts lung function. In Aim 3, we will determine if IL-13 inhibition reduces PDGF expression in the lung and ultimately improves lung function as compared to corticosteroids. The strength of this work is that we will relate the pathologic airway changes determined ex vivo to measures of large and small airway function in vivo in order to predict which asthmatic subjects will suffer the greatest physiological consequences of airway remodeling. This proposal will also determine whether PDGF inhibition could provide important adjuvant therapy for the treatment of severe asthmatics by limiting structural changes that result from activity of this pathway.

描述（由申请人提供）：哮喘中的气道重塑是随着时间的推移发生永久性结构变化的过程，导致固定气道阻塞的一部分，从而导致肺功能下降和对药物的反应性降低。我们已经表明，哮喘患者的近端肺和远端肺均发生气道炎症，并且我们提出重塑发生在两个肺室中。该提案的总体目标是检查导致整个肺部气道成纤维细胞生长和基质表达失调的关键途径，从而导致哮喘气道重塑。将炎症与气道结构变化联系起来的一种细胞类型是气道成纤维细胞。血小板衍生生长因子 (PDGF) 是由成纤维细胞产生的介质，由 IL-13 诱导，有助于组织修复。在初步研究中，我们证明了从正常受试者和哮喘受试者气道中培养的原代成纤维细胞的重要差异。从哮喘气道中分离出的原代成纤维细胞在关键的促有丝分裂 PDGF 通路中表现出严重紊乱。我们发现，TH2 细胞因子导致 PDGF 产生增加，PDGF 受体同种型的表达发生改变，以及 PDGF 导致的基质表达发生变化。此外，与正常对照组的成纤维细胞相比，皮质类固醇可以促进从轻度和重度哮喘患者中分离的成纤维细胞的生长。当 PDGF 被抑制时，这种作用就会消失。待检验的假设是 TH2 环境诱导血小板衍生生长因子 (PDGF) 的表达； PDGF 通过增加气道成纤维细胞生长和胶原表达以及减少近端和远端肺中的弹性蛋白表达来增强哮喘气道重塑过程。这些过程导致肺功能下降、气道塌陷和弹性反冲力丧失。皮质类固醇是治疗哮喘的主要药物，它不会抑制而是增强这些过程。为了检验这一假设，我们将招募患有轻度和重度哮喘的受试者以及正常对照者，他们将接受支气管镜检查以及近端（支气管内）和远端（经支气管）肺活检。我们将确定肺中 PDGF 的表达，以及其表达是否受 IL-13 调节（具体目标 1）。在具体目标 2 中，我们将确定 PDGF 调节整个肺部的成纤维细胞胶原蛋白和弹性蛋白表达，并且这种调节可预测肺功能。在目标 3 中，我们将确定与皮质类固醇相比，IL-13 抑制是否会降低肺中 PDGF 的表达并最终改善肺功能。这项工作的优势在于，我们将离体确定的病理性气道变化与体内大、小气道功能的测量联系起来，以预测哪些哮喘受试者将遭受气道重塑的最大生理后果。该提案还将确定 PDGF 抑制是否可以通过限制该通路活性导致的结构变化，为严重哮喘的治疗提供重要的辅助治疗。