Ligand-Receptor Segregation and Airway Remodeling

描述(申请人提供)：哮喘是一种异质性的呼吸道疾病，以慢性炎症、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为特征。呼吸道上皮的功能主要是作为屏障，阻止吸入的颗粒物、病毒和污染物进入肺部。上皮极化的本质是紧密连接起到将顶膜及其成分与基侧膜及其成分分开的功能。我们的初步数据提供了一项新的观察，解释了人类呼吸道上皮细胞如何在保持低细胞增殖率的同时，结构性地表达有丝分裂配体(hereglin-α)及其受体(ErbB)，从而突出了这一屏障的重要性。ErbB受体和hereglin-α的免疫定位表明hereglin-α定位于顶室，而erbB受体定位于基底膜。上皮损伤会导致受体的激活。这一范例作为一个强大的系统，能够在上皮完整性受到损害时被激活。因此，我们的主要假设是，气道上皮完整性的改变允许哮喘呼吸道表面液体(ASL)中存在的Hereglin-α和其他因子的基底侧方进入，这可能在哮喘的发病机制中发挥重要作用。我们建议研究三个特定的目标：1.呼吸道上皮细胞是否将配体与受体分离？2.非机械性损伤是否破坏了呼吸道上皮细胞屏障，使配体与受体相互作用？我们将调查两个主要假设。3.哮喘患者的呼吸道上皮细胞重塑是否是配体改变的结果：受体分离？我们的初步数据表明，气道上皮屏障的破坏导致了HERGOL-α介导的上皮细胞增殖和肥大，这是哮喘气道重塑的两个特征。我们推测，在哮喘的呼吸道中，上皮屏障的改变在气道上皮细胞重塑中起核心作用。

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.