Ligand-Receptor Segregation and Airway Remodeling

描述（由申请方提供）：哮喘是一种异质性气道疾病，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。气道上皮主要起屏障作用，防止吸入的颗粒物、病毒和污染物进入肺。上皮的极化性质使得紧密连接起将顶膜及其组分与基底侧膜及其组分分离的作用。我们的初步数据提供了新的观察结果，解释了人类气道上皮细胞如何组成性表达促有丝分裂配体（heregulin-alpha）及其受体（erbB），同时保持低细胞增殖率，这一屏障的重要性得到了强调。erbB受体和heregulin-alpha的免疫定位表明heregulin-alpha定位于顶室，erbB受体定位于基底外侧膜。上皮损伤导致受体的激活。这种模式作为一个强大的系统，能够被激活的即时上皮完整性受到损害。因此，我们的总体假设是，气道上皮完整性的改变允许基底外侧的heregulin-alpha和其他因素存在于哮喘气道表面液体（ASL），这可能在哮喘的发病机制中发挥重要作用。我们建议调查三个具体目标：1。气道上皮细胞能将配体与受体分离吗？2.非机械性损伤是否破坏了气道上皮屏障，使配体：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-alpha介导的上皮增生和肥大，这是哮喘气道重塑的两个标志。我们推测在哮喘气道中，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.