Department of Respiratory Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Respiratory Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Allergy Clin Immunol. 2021 Nov;148(5):1236-1248. doi: 10.1016/j.jaci.2020.12.653. Epub 2021 Feb 6.
Asthma is a heterogeneous disease with differences in onset, severity, and inflammation. Bronchial epithelial cells (BECs) contribute to asthma pathophysiology.
We determined whether transcriptomes of BECs reflect heterogeneity in inflammation and severity in asthma, and whether this was affected in BECs from patients with severe asthma after their regeneration by bronchial thermoplasty.
RNA sequencing was performed on BECs obtained by bronchoscopy from healthy controls (n = 16), patients with mild asthma (n = 17), patients with moderate asthma (n = 5), and patients with severe asthma (n = 17), as well as on BECs from treated and untreated airways of the latter (also 6 months after bronchial thermoplasty) (n = 23). Lipidome and metabolome analyses were performed on cultured BECs from healthy controls (n = 7); patients with severe asthma (n = 9); and, for comparison, patients with chronic obstructive pulmonary disease (n = 7).
Transcriptome analysis of BECs from patients showed a reduced expression of oxidative phosphorylation (OXPHOS) genes, most profoundly in patients with severe asthma but less profoundly and more heterogeneously in patients with mild asthma. Genes related to fatty acid metabolism were significantly upregulated in asthma. Lipidomics revealed enhanced levels of lipid species (phosphatidylcholines, lysophosphatidylcholines. and bis(monoacylglycerol)phosphate), whereas levels of OXPHOS metabolites were reduced in BECs from patients with severe asthma. BECs from patients with mild asthma characterized by hyperresponsive production of mediators implicated in neutrophilic inflammation had decreased expression of OXPHOS genes compared with that in BECs from patients with mild asthma with normoresponsive production. BECs obtained after thermoplasty had significantly increased expression of OXPHOS genes and decreased expression of fatty acid metabolism genes compared with BECs obtained from untreated airways.
BECs in patients with asthma are metabolically different from those in healthy individuals. These differences are linked with inflammation and asthma severity, and they can be reversed by bronchial thermoplasty.
哮喘是一种具有不同发病、严重程度和炎症表现的异质性疾病。支气管上皮细胞（BEC）参与哮喘的病理生理学过程。
我们旨在确定 BEC 的转录组是否反映了哮喘炎症和严重程度的异质性，以及在经过支气管热成形术再生后，严重哮喘患者的 BEC 是否会受到影响。
通过支气管镜从健康对照者（n=16）、轻度哮喘患者（n=17）、中度哮喘患者（n=5）和重度哮喘患者（n=17）中获取 BEC，并对其进行 RNA 测序，同时对后者经治疗和未经治疗的气道（同样在支气管热成形术后 6 个月）的 BEC 进行测序（n=23）。对健康对照者（n=7）、重度哮喘患者（n=9）以及为比较目的而纳入的慢性阻塞性肺疾病患者（n=7）的培养 BEC 进行脂质组学和代谢组学分析。
患者 BEC 的转录组分析显示，氧化磷酸化（OXPHOS）基因的表达降低，在重度哮喘患者中最为明显，但在轻度哮喘患者中则降低程度较轻且更具异质性。与脂肪酸代谢相关的基因在哮喘中显著上调。脂质组学显示，脂质种类（磷脂酰胆碱、溶血磷脂酰胆碱和双（单酰基甘油）磷酸）水平升高，而重度哮喘患者 BEC 中的 OXPHOS 代谢物水平降低。与轻度哮喘患者中具有正常反应性的介质产生者相比，具有高反应性介质产生特征的轻度哮喘患者的 BEC 中 OXPHOS 基因的表达降低。与未经治疗的气道相比，热成形术后获得的 BEC 的 OXPHOS 基因表达显著增加，脂肪酸代谢基因表达显著降低。
哮喘患者的 BEC 在代谢上与健康个体不同。这些差异与炎症和哮喘严重程度有关，并且可以通过支气管热成形术逆转。
