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的永久性结构变化的过程，导致固定气道阻塞的成分，可导致肺功能降低和对药物的反应性降低。我们已经表明，气道炎症发生在哮喘的近端和远端肺中，我们建议在两个肺部室内发生重塑。该提案的总体目标是检查临界途径，导致整个肺中气道成纤维细胞生长和基质表达失调，从而导致气道重塑哮喘。将炎症与结构气道变化联系起来的细胞类型是气道成纤维细胞。血小板衍生的生长因子（PDGF）是由成纤维细胞产生的介体，由IL-13诱导，在组织修复中发挥了作用。在初步研究中，我们证明了从正常和哮喘受试者的气道培养的原代成纤维细胞中的重要差异。从哮喘气道中分离出的原发性成纤维细胞在关键有丝分裂PDGF途径中表现出重大干扰。我们显示，PDGF响应Th2细胞因子，PDGF受体同工型的表达改变以及响应PDGF的矩阵表达的变化而增加了PDGF的产生。此外，与正常对照组的成纤维细胞相比，皮质类固醇从轻度和严重哮喘患者中分离出的成纤维细胞的生长。抑制PDGF时，这种效果被废除。要检验的假设是TH2环境诱导血小板衍生的生长因子（PDGF）的表达。 PDGF通过增加气道成纤维细胞生长和胶原蛋白表达以及降低近端和远端肺远端弹性蛋白表达来增强哮喘中的气道重塑过程。这些过程导致肺功能，气道可折叠性和弹性后坐力丧失的降低。皮质类固醇是哮喘治疗的主要疗法，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严重哮喘和正常对照的受试者，这些受试者将接受支气管镜检查，并近端（内断层）和远端（经支撑）肺活检。我们将确定肺中的PDGF表达，以及它的表达是否由IL-13调节（特定目标1）。在特定目标2中，我们将确定PDGF在整个肺部调节成纤维细胞胶原蛋白和弹性蛋白表达，并且该调节预测肺功能。在AIM 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的PDGF表达，并最终改善肺功能。这项工作的优势在于，我们将将确定的离体变化与体内大型和小气道功能的度量相关联，以预测哪些哮喘受试者将遭受气道重塑的最大生理后果。该提案还将通过限制该途径活动的结构变化来确定PDGF抑制是否可以为严重哮喘患者提供重要的辅助治疗。