Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA USA.
Constellation Pharmaceuticals, Inc., Cambridge, MA USA.
Sci Rep. 2017 Feb 24;7:43139. doi: 10.1038/srep43139.
Atopic asthma is a prevalent respiratory disease that is characterized by inflammation, mucus hypersecretion, and airway hyperresponsiveness. The complexity of this heterogeneous disorder has commanded the need to better define asthma phenotypes based on underlying molecular mechanisms of disease. Although classically viewed as a type 2-regulated disease, type 17 helper T (Th17) cells are known to be influential in asthma pathogenesis, predominantly in asthmatics with neutrophilia and severe refractory disease. Bromodomain and extra-terminal domain (BET) chromatin adaptors serve as immunomodulators by directly regulating Th17 responses and Th17-mediated pathology in murine models of autoimmunity and infection. Based on this, we hypothesized that BET proteins may also play an essential role in neutrophil-dominant allergic airway disease. Using a murine model of neutrophil-dominant allergic airway disease, we demonstrate that BET inhibition limits pulmonary inflammation and alters the Th17-related inflammatory milieu in the lungs. In addition, inhibition of BET proteins improved lung function (specifically quasi-static lung compliance and tissue elastance) and reduced mucus production in airways. Overall, these studies show that BET proteins may have a critical role in asthma pathogenesis by altering type 17 inflammation, and thus interfering with BET-dependent chromatin signaling may provide clinical benefits to patients suffering from asthma.
特应性哮喘是一种常见的呼吸道疾病，其特征为炎症、黏液高分泌和气道高反应性。这种异质性疾病的复杂性要求根据疾病的潜在分子机制更好地定义哮喘表型。尽管特应性哮喘通常被视为 2 型调节疾病，但已知 17 型辅助性 T（Th17）细胞在哮喘发病机制中具有重要作用，主要在伴有嗜中性粒细胞增多和严重难治性疾病的哮喘患者中。溴结构域和末端外结构域（BET）染色质衔接蛋白作为免疫调节剂，通过直接调节自身免疫和感染的小鼠模型中的 Th17 反应和 Th17 介导的病理学，发挥作用。基于此，我们假设 BET 蛋白也可能在嗜中性粒细胞为主的变应性气道疾病中发挥重要作用。我们使用嗜中性粒细胞为主的变应性气道疾病的小鼠模型，证明 BET 抑制可限制肺部炎症并改变肺部的 Th17 相关炎症环境。此外，BET 蛋白的抑制可改善肺功能（特别是准静态肺顺应性和组织弹性）并减少气道中的黏液产生。总的来说，这些研究表明 BET 蛋白可能通过改变 17 型炎症在哮喘发病机制中起关键作用，因此干扰 BET 依赖性染色质信号可能为患有哮喘的患者带来临床益处。
