DP2 antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment
DP2 antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment
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DOI：
10.1126/scitranslmed.aao6451
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发表时间：
2019-02-13
影响因子：
17.1
通讯作者：
Brightling, Christopher E.
中科院分区：
文献类型：
--
作者：
Saunders, Ruth;Kaul, Himanshu;Brightling, Christopher E.
气道平滑肌质量增加是哮喘气道重塑的一个特征，是气流受限的最强预测因子，并有助于哮喘相关的发病率和死亡率。目前还没有已知的治疗哮喘的药物会影响气道平滑肌质量。尽管越来越多的证据表明前列腺素D-2 2型受体（DP2）在气道结构细胞和炎症细胞中表达，但很少有研究关注DP2在气道平滑肌细胞中的表达和功能。我们报道，DP2拮抗剂fevipiprant在参加之前的随机安慰剂对照试验的哮喘患者的支气管活检中减少了气道平滑肌质量。我们开发了一个计算模型来捕捉气道重塑。我们的模型预测，仅气道嗜酸性粒细胞减少不足以解释临床观察到的气道平滑肌质量减少，而气道平滑肌细胞或其前体向气道平滑肌束（构成气道平滑肌层）的募集没有同时减少。我们通过实验证实，在气道平滑肌细胞培养模型中，dp2特异性拮抗剂可以抑制气道平滑肌的体外迁移。我们的分析表明，fevipiprant通过对DP2的拮抗作用，通过减少气道嗜酸性粒细胞，同时减少肌成纤维细胞和纤维细胞向气道平滑肌束的募集，减少哮喘患者气道平滑肌质量。因此，Fevipiprant可能是一种改善哮喘气道重塑的潜在疗法。
Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D-2 type 2 receptor (DP2) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP2 in airway smooth muscle cells. We report that the DP2 antagonist fevipiprant reduced airway smooth muscle mass in bronchial biopsies from patients with asthma who had participated in a previous randomized placebo-controlled trial. We developed a computational model to capture airway remodeling. Our model predicted that a reduction in airway eosinophilia alone was insufficient to explain the clinically observed decrease in airway smooth muscle mass without a concomitant reduction in the recruitment of airway smooth muscle cells or their precursors to airway smooth muscle bundles that comprise the airway smooth muscle layer. We experimentally confirmed that airway smooth muscle migration could be inhibited in vitro using DP2-specific antagonists in an airway smooth muscle cell culture model. Our analyses suggest that fevipiprant, through antagonism of DP2, reduced airway smooth muscle mass in patients with asthma by decreasing airway eosinophilia in concert with reduced recruitment of myofibroblasts and fibrocytes to the airway smooth muscle bundle. Fevipiprant may thus represent a potential therapy to ameliorate airway remodeling in asthma.