Tu Xiaofan, Kim Richard Y, Brown Alexandra C, de Jong Emma, Jones-Freeman Bernadette, Ali Md Khadem, Gomez Henry M, Budden Kurtis F, Starkey Malcolm R, Cameron Guy J M, Loering Svenja, Nguyen Duc H, Nair Prema Mono, Haw Tatt Jhong, Alemao Charlotte A, Faiz Alen, Tay Hock L, Wark Peter A B, Knight Darryl A, Foster Paul S, Bosco Anthony, Horvat Jay C, Hansbro Philip M, Donovan Chantal
Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia.
Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia; Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, Australia.
J Allergy Clin Immunol. 2022 Oct;150(4):817-829.e6. doi: 10.1016/j.jaci.2022.04.032. Epub 2022 May 25.
Asthma and chronic obstructive pulmonary disease (COPD) are common chronic respiratory diseases, and some patients have overlapping disease features, termed asthma-COPD overlap (ACO). Patients characterized with ACO have increased disease severity; however, the mechanisms driving this have not been widely studied.
This study sought to characterize the phenotypic and transcriptomic features of experimental ACO in mice induced by chronic house dust mite antigen and cigarette smoke exposure.
Female BALB/c mice were chronically exposed to house dust mite antigen for 11 weeks to induce experimental asthma, cigarette smoke for 8 weeks to induce experimental COPD, or both concurrently to induce experimental ACO. Lung inflammation, structural changes, and lung function were assessed. RNA-sequencing was performed on separated airway and parenchyma lung tissues to assess transcriptional changes. Validation of a novel upstream driver SPI1 in experimental ACO was assessed using the pharmacological SPI1 inhibitor, DB2313.
Experimental ACO recapitulated features of both asthma and COPD, with mixed pulmonary eosinophilic/neutrophilic inflammation, small airway collagen deposition, and increased airway hyperresponsiveness. Transcriptomic analysis identified common and distinct dysregulated gene clusters in airway and parenchyma samples in experimental asthma, COPD, and ACO. Upstream driver analysis revealed increased expression of the transcription factor Spi1. Pharmacological inhibition of SPI1 using DB2313, reduced airway remodeling and airway hyperresponsiveness in experimental ACO.
A new experimental model of ACO featuring chronic dual exposures to house dust mite and cigarette smoke mimics key disease features observed in patients with ACO and revealed novel disease mechanisms, including upregulation of SPI1, that are amenable to therapy.
哮喘和慢性阻塞性肺疾病（COPD）是常见的慢性呼吸道疾病，一些患者具有重叠的疾病特征，称为哮喘-COPD重叠综合征（ACO）。具有ACO特征的患者疾病严重程度增加；然而，导致这种情况的机制尚未得到广泛研究。
本研究旨在表征由慢性屋尘螨抗原和香烟烟雾暴露诱导的实验性ACO在小鼠中的表型和转录组特征。
雌性BALB/c小鼠长期暴露于屋尘螨抗原11周以诱导实验性哮喘，暴露于香烟烟雾8周以诱导实验性COPD，或同时暴露于两者以诱导实验性ACO。评估肺部炎症、结构变化和肺功能。对分离的气道和肺实质组织进行RNA测序以评估转录变化。使用药理学SPI1抑制剂DB2313评估实验性ACO中一种新型上游驱动因子SPI1的验证。
实验性ACO概括了哮喘和COPD的特征，伴有混合性肺嗜酸性粒细胞/中性粒细胞炎症、小气道胶原沉积和气道高反应性增加。转录组分析确定了实验性哮喘、COPD和ACO气道和实质样本中常见和不同的失调基因簇。上游驱动因子分析显示转录因子Spi1表达增加。使用DB2313对SPI1进行药理学抑制可减少实验性ACO中的气道重塑和气道高反应性。
一种新的ACO实验模型，其特点是长期双重暴露于屋尘螨和香烟烟雾，模拟了ACO患者中观察到的关键疾病特征，并揭示了新的疾病机制，包括SPI1上调，这些机制适合治疗。
