Sánchez-Ovando Stephany, Simpson Jodie L, Barker Daniel, Baines Katherine J, Wark Peter A B
Priority Research Centre for Healthy Lungs, Faculty of Health and Medicine, University of Newcastle, NSW, Australia.
Faculty of Health and Medicine, University of Newcastle, NSW, Australia.
Clin Exp Allergy. 2021 Oct;51(10):1279-1294. doi: 10.1111/cea.13986. Epub 2021 Jul 17.
Severe asthma is a complex disease. Transcriptomic profiling has contributed to understanding the pathogenesis of asthma, especially type-2 inflammation. However, there is still poor understanding of non-type-2 asthma, and consequently, there are limited treatment options.
The aim of this study was to identify differentially expressed genes (DEGs) and pathways in endobronchial biopsies associated with inflammatory phenotypes of severe asthma.
This cross-sectional study examined endobronchial biopsies from 47 adults with severe asthma (neutrophilic asthma (NA) n = 9, eosinophilic asthma (EA) n = 22 and paucigranulocytic asthma (PGA) n = 16) and 13 healthy controls (HC). RNA was extracted and transcriptomic profiles generated (Illumina Humanref-12 V4) and analysed using GeneSpring GX14.9.1. Pathway identification using Ingenuity Pathway Analysis.
NA had the most distinct profile, with signature of 60 top-ranked DEGs (FC >±2) including genes associated with innate immunity response, neutrophil degranulation and IL-10 signalling. NA presented enrichment to pathways previously linked to neutrophilic inflammation; dendritic cell maturation, Th1, TREM1, inflammasome, Th17 and p38 MAPK, as well as novel links to neuroinflammation, NFAT and PKCθ signalling. EA presented similar transcriptomic profiles to PGA and HC. Despite the higher proportion of bacterial colonization in NA, no changes were observed in the transcriptomic profiles of severe asthma culture positive compared with severe asthma culture negative.
CONCLUSIONS & CLINICAL RELEVANCE: NA features a distinct transcriptomic profile with seven pathways enriched in NA compared to EA, PGA and HC. All those with severe asthma had significant enrichment for SUMOylation, basal cell carcinoma signalling and Wnt/β-catenin pathways compared to HC, despite high-dose inhaled corticosteroids. These findings contribute to the understanding of mechanistic pathways in endobronchial biopsies associated with NA and identify potential novel treatment targets for severe asthma.
重度哮喘是一种复杂的疾病。转录组分析有助于理解哮喘的发病机制，尤其是2型炎症。然而，对于非2型哮喘仍了解不足，因此治疗选择有限。
本研究旨在识别与重度哮喘炎症表型相关的支气管内活检组织中的差异表达基因（DEG）和信号通路。
这项横断面研究检查了47例重度哮喘成人（嗜中性粒细胞性哮喘（NA）9例、嗜酸性粒细胞性哮喘（EA）22例和少粒细胞性哮喘（PGA）16例）以及13名健康对照（HC）的支气管内活检组织。提取RNA并生成转录组图谱（Illumina Humanref-12 V4），使用GeneSpring GX14.9.1进行分析。使用Ingenuity Pathway Analysis进行信号通路识别。
NA具有最独特的图谱，有60个排名靠前的DEG（FC>±2）特征，包括与固有免疫反应、中性粒细胞脱颗粒和IL-10信号相关的基因。NA表现出与先前嗜中性粒细胞炎症相关的信号通路富集；树突状细胞成熟、Th1、TREM1、炎性小体、Th17和p38 MAPK，以及与神经炎症、NFAT和PKCθ信号的新联系。EA呈现出与PGA和HC相似的转录组图谱。尽管NA中细菌定植比例较高，但重度哮喘培养阳性与重度哮喘培养阴性的转录组图谱未观察到变化。
与EA、PGA和HC相比，NA具有独特的转录组图谱，有7条信号通路在NA中富集。与HC相比，所有重度哮喘患者尽管使用了高剂量吸入性糖皮质激素，但SUMO化、基底细胞癌信号和Wnt/β-连环蛋白信号通路均有显著富集。这些发现有助于理解与NA相关的支气管内活检组织中的机制信号通路，并确定重度哮喘潜在的新治疗靶点。
