哮喘和 COPD 重叠综合症新模型中的气道和实质组织的转录组学
2022/06/17
摘要
背景：哮喘和慢性阻塞性肺疾病（COPD）是常见的慢性呼吸系统疾病，一些患者有重叠的疾病特征，称为哮喘-COPD重叠综合症（ACO）。以ACO为特征的患者疾病程度更为严重，但其机制尚未得到广泛研究。
目的：研究慢性屋尘螨（HDM）提取物和香烟烟雾（CS）暴露诱导的小鼠试验性ACO的表型和转录组学特征。
方法：雌性BALB/c小鼠长期暴露于HDM 11周以诱导试验性哮喘，CS 8周以诱导试验性COPD，或同时暴露于HDM和CS以诱导试验性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，以评估其转录组差异。使用药物SPI1抑制剂DB2313验证一种新的上游驱动因子SPI1在试验性ACO中的作用。
结果：试验的ACO包括哮喘和COPD的特征，包括混合性肺嗜酸性/中性炎症、小气道胶原沉积和气道高反应性（AHR）增加。转录组学分析确定了试验性哮喘、COPD和ACO患者气道和肺实质样本中常见和不同的失调基因簇。上游驱动因素分析显示转录因子SPI 1的表达增加。使用DB2313对SPI1进行药理学抑制，减少试验性ACO的气道重塑和AHR。
结论：一种新的慢性双重暴露于HDM和CS的ACO模型模拟了ACO患者的主要疾病特征，并揭示了新的疾病机制，包括SPI1的上调，这些机制可能是新的治疗靶点。
Airway and parenchymal transcriptomics in a novel model of asthma and COPD overlap
Xiaofan Tu, Richard Y Kim, Alexandra C Brown
Abstrast
Background: 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.
Objective: To characterize the phenotypic and transcriptomic features of experimental ACO in mice induced by chronic house dust mite (HDM) extract and cigarette smoke (CS) exposure.
Methods: Female BALB/c mice were chronically exposed to HDM for 11 weeks to induce experimental asthma, CS 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 parenchymal lung tissues to assess transcriptional changes. Validation of a novel upstream driver SPI1 in experimental ACO was assessed using the pharmacological SPI1 inhibitor, DB2313.
Results: Experimental ACO recapitulated features of both asthma and COPD, with mixed pulmonary eosinophilic/neutrophilic inflammation, small airway collagen deposition and increased airway hyperresponsiveness (AHR). Transcriptomic analysis identified common and distinct dysregulated gene clusters in airway and parenchymal 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 AHR in experimental ACO.
Conclusion: A new experimental model of ACO featuring chronic dual exposures to HDM and CS mimics key disease features observed in patients with ACO and revealed novel disease mechanisms, including upregulation of SPI1, that are amenable to therapy.
背景：哮喘和慢性阻塞性肺疾病（COPD）是常见的慢性呼吸系统疾病，一些患者有重叠的疾病特征，称为哮喘-COPD重叠综合症（ACO）。以ACO为特征的患者疾病程度更为严重，但其机制尚未得到广泛研究。
目的：研究慢性屋尘螨（HDM）提取物和香烟烟雾（CS）暴露诱导的小鼠试验性ACO的表型和转录组学特征。
方法：雌性BALB/c小鼠长期暴露于HDM 11周以诱导试验性哮喘，CS 8周以诱导试验性COPD，或同时暴露于HDM和CS以诱导试验性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，以评估其转录组差异。使用药物SPI1抑制剂DB2313验证一种新的上游驱动因子SPI1在试验性ACO中的作用。
结果：试验的ACO包括哮喘和COPD的特征，包括混合性肺嗜酸性/中性炎症、小气道胶原沉积和气道高反应性（AHR）增加。转录组学分析确定了试验性哮喘、COPD和ACO患者气道和肺实质样本中常见和不同的失调基因簇。上游驱动因素分析显示转录因子SPI 1的表达增加。使用DB2313对SPI1进行药理学抑制，减少试验性ACO的气道重塑和AHR。
结论：一种新的慢性双重暴露于HDM和CS的ACO模型模拟了ACO患者的主要疾病特征，并揭示了新的疾病机制，包括SPI1的上调，这些机制可能是新的治疗靶点。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(The Journal of allergy and clinical immunology 2022 May 25; doi:10.1016/j.jaci.2022.04.032 IF：10.793)
(The Journal of allergy and clinical immunology 2022 May 25; doi:10.1016/j.jaci.2022.04.032 IF：10.793)
Airway and parenchymal transcriptomics in a novel model of asthma and COPD overlap
Xiaofan Tu, Richard Y Kim, Alexandra C Brown
Abstrast
Background: 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.
Objective: To characterize the phenotypic and transcriptomic features of experimental ACO in mice induced by chronic house dust mite (HDM) extract and cigarette smoke (CS) exposure.
Methods: Female BALB/c mice were chronically exposed to HDM for 11 weeks to induce experimental asthma, CS 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 parenchymal lung tissues to assess transcriptional changes. Validation of a novel upstream driver SPI1 in experimental ACO was assessed using the pharmacological SPI1 inhibitor, DB2313.
Results: Experimental ACO recapitulated features of both asthma and COPD, with mixed pulmonary eosinophilic/neutrophilic inflammation, small airway collagen deposition and increased airway hyperresponsiveness (AHR). Transcriptomic analysis identified common and distinct dysregulated gene clusters in airway and parenchymal 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 AHR in experimental ACO.
Conclusion: A new experimental model of ACO featuring chronic dual exposures to HDM and CS mimics key disease features observed in patients with ACO and revealed novel disease mechanisms, including upregulation of SPI1, that are amenable to therapy.
