Role of Th2 and non-Th2 Inflammation in Airway Smooth Muscle Remodeling in Asthma

描述(由申请人提供)： 在呼吸道中过度聚集的平滑肌(平滑肌重塑)可能导致哮喘的气道阻塞和疾病进展，最近的研究已经确定了可能有助于这一过程的因素。与此同时，基础免疫学研究表明，哮喘本质上是一种由辅助性T细胞2型(Th2)驱动的炎症性疾病。然而，Th2炎症是否是导致人类哮喘气道重塑的主要因素尚不确定。我们的初步数据表明，呼吸道Th2炎症的典型介质--白介素13(IL-13)只在一小部分哮喘患者中驱动炎症。这种由IL-13驱动的哮喘占我们哮喘患者的一半，代表了一种不同的临床和病理表型。在平滑肌方面，我们的初步数据显示，在“IL-13驱动”的哮喘中，重构显著增加，这表明Th2炎症直接参与了人类哮喘的平滑肌重构。我们的数据还确定了一种基质细胞蛋白Periostin，它可能是一种介体，可能将IL-13驱动的炎症与哮喘的气道重塑联系起来。另一方面，我们的数据表明，在“非IL-13驱动的”哮喘中也可能存在一定程度的平滑肌重塑，这意味着在一些患者中存在额外的非Th2驱动的通路。如果是这样的话，这意味着ASM重塑是所有哮喘表型的共同的基本异常。在这些数据的基础上，我们提出了三个目标来解决以下假设：1)IL-13驱动的炎症促进ASM重塑，2)驻留肺细胞对IL-13的反应所分泌的Periostin介导了“IL-13驱动”的哮喘的ASM重塑，3)额外的非IL-13驱动的通路有助于某些患者的ASM重塑，这些路径可以用翻译和基因组方法来识别。这些研究将在体内通过应用支气管镜检查、基于设计的体视学、激光捕获显微解剖和基因组学在哮喘患者和健康对照的详细研究中进行，并在体外使用细胞培养模型进行。这些研究将利用研究人类ASM的创新方法，并解决炎症、重塑和ASM合成功能之间的相互作用。重要的是，我们的成果将解决在该领域取得进展的一个关键障碍，无论结果如何。如果在“IL-13驱动的哮喘”中ASM重塑增强，那么针对Th2炎症或特定下游介质(如Periostin)的策略应能改善ASM重塑。然而，如果ASM重塑也可以发生在“非IL-13驱动的”哮喘中，那么我们的研究将通过关注哮喘中ASM功能障碍的非Th2途径来指导该领域的进一步研究，这可能是新的，并且不是当前治疗的靶点。(摘要结束)

DESCRIPTION (provided by applicant): Excessive accumulation of smooth muscle in the airway (smooth muscle remodeling), may contribute to airway obstruction and disease progression in asthma, and recent studies have identified factors that could contribute to this process. At the same time, basic immunological research suggests that asthma is fundamentally a T helper type 2 (Th2)-driven inflammatory disease. However, whether Th2 inflammation is the major factor underlying airway remodeling in human asthma is uncertain. Our preliminary data demonstrate that the canonical mediator of Th2 inflammation in the airway, interleukin-13 (IL-13), drives inflammation in only a subset of patients with asthma. This subset with "IL-13-driven" asthma comprises half of our asthmatics and represents a distinct clinical and pathological phenotype. With regard to smooth muscle, our preliminary data indicate that remodeling is markedly increased in "IL-13 driven" asthma, suggesting that Th2 inflammation contributes directly to smooth muscle remodeling in human asthma. Our data also identify a matricellular protein, periostin, as a mediator which may link IL-13 driven inflammation to airway remodeling in asthma. On the other hand, our data suggest that some degree of smooth muscle remodeling may be present in "non-IL-13 driven" asthma as well, implying additional non-Th2-driven pathways in some patients. If so, this implies that ASM remodeling is a fundamental abnormality common to all phenotypes of asthma. On the basis of these data, we propose three aims to address the following hypotheses: 1) that IL-13-driven inflammation enhances ASM remodeling, 2) that periostin, secreted by resident lung cells in response to IL-13, mediates ASM remodeling in "IL-13 driven" asthma, and 3) that additional non-IL-13 driven pathways contribute to ASM remodeling in some patients and that these pathways can be identified using translational and genomic approaches. These studies will be performed in vivo by applying bronchoscopy, design-based stereology, laser capture microdissection and genomics in a detailed study of asthmatics and healthy controls and in vitro using cell culture models. These studies will leverage innovative methodologies for the study of ASM in humans and address the interplay between inflammation, remodeling and ASM synthetic function. Importantly, our results will address a critical barrier to progress in the field, whatever the result. If ASM remodeling is enhanced in "IL- 13 driven asthma", then strategies that target Th2 inflammation or specific downstream mediators such as periostin, should improve ASM remodeling. However, if ASM remodeling can also occur in "non-IL-13-driven" asthma, then our studies will guide further research in the field by directing attention to non-Th2 pathways of ASM dysfunction in asthma which may be novel and are not targeted by current therapies. (End of Abstract)