Ligand-Receptor Segregation and Airway Remodeling

描述（由申请人提供）：哮喘是一种气道异质性疾病，其特征为慢性炎症、气道重塑、杯状细胞化生/增生、粘液分泌增加和支气管高反应性。气道上皮的功能主要是作为屏障，防止吸入的颗粒物、病毒和污染物进入肺部。上皮的极化特性使得紧密连接的功能将顶膜及其组成部分与底外侧膜及其组成部分分开。我们的初步数据提供的新观察结果强调了这一屏障的重要性，该数据解释了人类气道上皮如何在保持低细胞增殖率的同时组成性地表达有丝分裂配体（heregulin- α）及其受体（erbB）。erbB受体和heregulin- α的免疫定位表明heregulin- α定位于根尖室，erbB受体定位于基底外膜。上皮损伤导致受体的激活。这种模式作为一个强大的系统，能够在上皮完整性受损的瞬间被激活。因此，我们的总体假设是，气道上皮完整性的改变允许heregulin- α和哮喘气道表面液（ASL）中存在的其他因子从基底外侧进入，这可能在哮喘的发病机制中起重要作用。我们建议研究三个具体目标：1。气道上皮是否分离配体和受体？2. 非机械性损伤是否破坏气道上皮屏障以允许配体：受体相互作用？我们将研究两个主要假设。3. 哮喘气道上皮重塑是配体：受体分离改变的结果吗？我们的初步数据表明，气道上皮屏障的破坏导致heregulin- α介导的上皮增生和肥大，这是哮喘气道重塑的两个标志。我们假设在哮喘气道中，上皮屏障的改变在气道上皮重塑中起核心作用。

DESCRIPTION (provided by applicant): Asthma is a heterogeneous disease of the airways characterized by chronic inflammation, airway remodeling, goblet cell metaplasia/hyperplasia, increased mucus secretion and bronchial hyperresponsiveness. The airway epithelium functions primarily as a barrier, preventing access of inhaled particulate matter, viruses, and pollutants to the lung. The polarized nature of an epithelium is such that the tight junctions function to separate the apical membrane and its components from the basolateral membrane and its components. The importance of this barrier is highlighted by the novel observation provided by our preliminary data that explains how human airway epithelia can constitutively express both a mitogenic ligand (heregulin-alpha) and its receptors (erbB) while simultaneously maintaining a low rate of cellular proliferation. Immunolocalization of erbB receptors and heregulin-alpha suggests that heregulin-alpha localizes to the apical compartment and erbB receptors localize to the basolateral membrane. Epithelial injury results in activation of the receptors. This paradigm serves as a powerful system able to be activated the instant epithelial integrity is compromised. Thus, our overarching hypothesis is that alteration of airway epithelial integrity allows basolateral access of heregulin-alpha and other factors present in asthmatic airway surface liquid (ASL) and that this may play an important role in the pathogenesis of asthma. We propose to investigate three specific aims: 1. Do airway epithelia segregate ligand from receptor? 2. Is the airway epithelia barrier disrupted to allow ligand: receptor interaction by non-mechanical injuries? We will investigate two main hypotheses. 3. Is airway epithelial remodeling in asthma a consequence of altered ligand: receptor segregation? Our preliminary data suggests that disruption of the airway epithelial barrier results in a heregulin-alpha-mediated epithelial hyperplasia and hypertrophy, two hallmarks of airway remodeling in asthma. We hypothesize that in the asthmatic airways, alterations in the epithelial barrier play a central role in airway epithelial remodeling.