Epithelium-fibroblast interactions in response to allergic airway inflammation

哮喘患者的气道随着时间的推移发生了巨大的结构变化。这种重塑被认为是导致肺功能变化的原因，这种变化在患有这种疾病的人中经常观察到。然而，与正常的伤口修复相反，目前尚不清楚为什么在大多数哮喘患者中，炎症导致持续的重塑而不是自我限制的愈合过程。在这种情况下，排列在气道（上皮）上的细胞以及位于其正下方的细胞（成纤维细胞）是有助于这些过程的介质和结构基质蛋白的重要来源。在正常情况下，来自这些结构蛋白的信号通过特定的粘附分子传递到细胞。然而，在哮喘中，上皮细胞经常受损和脱落，成纤维细胞似乎增殖并发生外观变化。本项目旨在研究气道炎症后上皮细胞和成纤维细胞中特异性细胞粘附分子的表达和功能。具体而言，该提案旨在确定哪些粘附分子与基质蛋白的增殖和生产上调相关。我们还将研究两种新的介质的影响，被认为在重塑这些粘附分子的表达和功能中发挥作用。这些细胞的增殖和基质蛋白沉积的改变可能是气道壁增厚和高反应性的关键特征，而高反应性是哮喘的特征性特征。基质蛋白的沉积和分解的平衡由多种介质调节。确定是什么调节粘附分子的表达和活性是至关重要的，在确定如何正常的修复过程可能演变成气道壁重塑。

The airways of an asthmatic patient undergo dramatic structural changes over time. This remodelling is thought to be responsible for producing the changes in lung function that are frequently observed in someone with the disease. However, in contrast to normal wound repair, it is unclear why in the majority of asthmatics, inflammation leads to ongoing remodelling rather than a self limiting healing process. In this context, cells that line the airways (epithelium) as well as cells that sit immediately beneath them (fibroblasts) are important sources of mediators and structural matrix proteins that contribute to these processes. Under normal conditions, signals from these structural proteins are transmitted to the cells via specific adhesion molecules. However, in asthma epithelial cells are frequently damaged and detached, and fibroblasts appear to proliferate and undergo changes in their appearance. This projects aims to investigate the expression and function of specific cell adhesion molecules in the epithelium and fibroblasts following airway inflammation. Specifically, this proposal aims to determine which adhesion molecules are associated with upregulated proliferation and production of matrix proteins. We will also examine the effects of two novel mediators, thought to play a role in remodelling on the expression and function of these adhesion molecules. Proliferation of these cells and the altered deposition of matrix proteins may be a key feature of airway wall thickening and hyperreactivity that is a characteristic feature of asthma. The balance of deposition and breakdown of matrix proteins is regulated by a variety of mediators. Defining what regulates the expression and activity of adhesion molecules is of fundamental importance in determining how the normal repair processes may evolve into airway wall remodelling.