Dysregulated Airway Epithelial Signaling as a Driver of Airway Remodeling in Asthmatic Children

 描述（由申请人提供）：流行病学研究表明，与健康儿童相比，哮喘儿童在儿童期的肺功能较低，并持续到成年。哮喘儿童的支气管活检表明，气道重塑的特征，包括过度的上皮下细胞外基质沉积（如胶原蛋白、透明质酸），在儿童早期就已经存在。总之，这些数据表明，哮喘气道的早期结构变化可能有助于肺功能下降，这在哮喘自然史的早期表现出来。虽然吸入性皮质类固醇可降低发病率，但治疗不能改变哮喘的自然病程，也不能防止肺功能下降。对气道重塑机制的深入理解是未来临床干预措施发展的基础，以改变哮喘的自然病程并预防肺功能下降。气道上皮细胞是环境与宿主肺之间的第一个接触点。来自动物模型和人支气管活检的证据表明，支气管上皮分泌许多蛋白质，这些蛋白质可以调节肺成纤维细胞和气道重塑。我们的研究小组已经证明，与健康的上皮细胞相比，哮喘儿童的原代气道上皮细胞本质上表现出更高的候选促重塑因子表达。我们还报道，在共同培养的健康儿童气道上皮细胞显着下调参与气道重塑的细胞外基质成分的肺成纤维细胞表达。相反，当成纤维细胞与哮喘上皮细胞共培养时，这种下调显著较少。来自我们的人气道上皮细胞模型系统的初步数据表明，前列腺素E2（PGE 2）和激活素抑制剂卵泡抑素样3（FSTL 3）作为上皮分泌的蛋白质，其显著抑制成纤维细胞功能。我们建议使用创新的气道上皮细胞/成纤维细胞共培养模型系统与原代支气管上皮细胞从良好的特征哮喘和健康儿童来测试我们的假设，即在正常气道上皮源性刺激和抑制因子的平衡调节成纤维细胞，抑制气道间质细胞外基质沉积参与气道重塑。我们将检验我们的假设，即这些因子的表达在哮喘中失调，特别是TGF β 2和激活素A增加，以及哮喘上皮细胞PGE 2和FSTL 3表达减少，导致成纤维细胞增殖和细胞外基质表达增加。最后，我们将检验我们的假设，即哮喘共培养物中成纤维细胞增殖和细胞外基质成分的表达以及TGF β 2、激活素A、PGE 2和FSTL 3的上皮分泌与哮喘严重程度、哮喘恶化和/或哮喘儿童的肺功能相关，所述哮喘儿童捐献了用于共培养实验的气道上皮细胞。

 DESCRIPTION (provided by applicant): Epidemiologic studies have revealed that asthmatic children have lower lung function during childhood that persists into adulthood compared to healthy children. Bronchial biopsies from asthmatic children demonstrate that features of airway remodeling, including excessive sub-epithelial extracellular matrix deposition (e.g. collagens, hyaluronan), are already present in early childhood. Together, these data suggest that early structural changes in the asthmatic airway may contribute to lung function declines that manifest early in the natural history of asthma. Although inhaled corticosteroids reduce morbidity, treatment does not alter the natural history of asthma nor prevent decline in lung function. Improved understanding of mechanisms that drive airway remodeling is fundamental to the development of future clinical interventions to alter the natural course of asthma and prevent lung function decline. Airway epithelial cells are the first point of contact between the environment and the host lung. Evidence from animal models and human bronchial biopsies suggest that the bronchial epithelium secretes a number of proteins that may regulate lung fibroblasts and airway remodeling. Our group has demonstrated that primary airway epithelial cells from asthmatic children intrinsically exhibit greater expression of candidate pro-remodeling factors, when compared to healthy epithelial cells. We have also reported that in co-culture airway epithelial cells from healthy children markedly down-regulate lung fibroblast expression of extracellular matrix components involved in airway remodeling. In contrast, this down-regulation is significantly less when fibroblasts are co-cultured with asthmatic epithelial cells. Preliminary data from our human airway epithelial cell model systems suggest prostaglandin E2 (PGE2) and the activin inhibitor follistatin-like-3 (FSTL3) as epithelial-secreted proteins that ma tonically inhibit fibroblast function. We propose to use innovative airway epithelial cell/fibroblat co-culture model systems with primary bronchial epithelial cells from well-characterized asthmatic and healthy children to test our hypothesis that in normal airways a balance of epithelial-derived stimulatory and inhibitory factors regulates fibroblasts and inhibits airway interstitial extracellular matrix deposition involved in airway remodeling. We will test our hypothesis that expression of these factors is dysregulated in asthma, specifically with increased TGFß2 and activin A, as well as decreased PGE2 and FSTL3 expression by asthmatic epithelial cells, leading to increased fibroblast proliferation and extracellular matrix expression. Finally, we will test our hypotheses that fibroblast proliferation and expression of extracellular matrix constituents and epithelial secretion of TGFß2, activin A, PGE2 and FSTL3, in asthmatic co-cultures are associated with asthma severity, asthma exacerbations, and/or lung function among the asthmatic children who donated airway epithelial cells used in co-culture experiments.