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

描述（由申请人提供）： 气道中平滑肌的过度积聚（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导致这一过程的因素。与此同时，基础免疫学研究表明，哮喘从根本上说是一种辅助性T细胞2型（Th 2）驱动的炎症性疾病。然而，Th 2炎症是否是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，气道中Th 2炎症的典型介质白细胞介素-13（IL-13）仅在一部分哮喘患者中驱动炎症。这一“IL-13驱动”哮喘亚群占我们哮喘患者的一半，代表了独特的临床和病理表型。关于平滑肌，我们的初步数据表明，重塑在“IL-13驱动”哮喘中显著增加，表明Th 2炎症直接有助于人哮喘中的平滑肌重塑。我们的数据还确定了一种基质细胞蛋白，骨膜蛋白，作为一种介质，可能连接IL-13驱动的炎症气道重塑哮喘。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，这意味着在某些患者中存在额外的非Th 2驱动的途径。如果是这样，这意味着ASM重塑是所有哮喘表型共同的基本异常。在这些数据的基础上，我们提出了三个目标，以解决以下假设：1）IL-13驱动的炎症增强ASM重塑，2）在“IL-13驱动的”哮喘中，由驻留肺细胞响应于IL-13分泌的骨膜蛋白介导ASM重塑，和3）额外的非IL-13驱动的途径有助于一些患者的ASM重塑，并且这些途径可以使用翻译和基因组方法来鉴定。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、激光捕获显微切割和基因组学对哮喘患者和健康对照进行详细研究，并在体外使用细胞培养模型进行。这些研究将利用人类ASM研究的创新方法，并解决炎症，重塑和ASM合成功能之间的相互作用。重要的是，无论结果如何，我们的结果将解决该领域进展的关键障碍。如果ASM重塑在“IL- 13驱动的哮喘”中增强，则靶向Th 2炎症或特定下游介质如骨膜蛋白的策略应改善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将注意力转向哮喘中ASM功能障碍的非Th 2途径来指导该领域的进一步研究，这可能是新颖的，并且不是当前治疗的目标。(End摘要）

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)