Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval (IUCPQ-UL), 2725 Chemin Sainte-Foy, Québec, QC, G1V 4G5, Canada.
IRMB, Univ Montpellier, INSERM, CHU Montpellier, Montpellier, France.
Respir Res. 2023 Nov 23;24(1):294. doi: 10.1186/s12931-023-02604-1.
Severe asthma affects a small proportion of asthmatics but represents a significant healthcare challenge. Bronchial thermoplasty (BT) is an interventional treatment approach preconized for uncontrolled severe asthma after considering biologics therapy. It was showed that BT long-lastingly improves asthma control. These improvements seem to be related to the ability of BT to reduce airway smooth muscle remodeling, reduce the number of nerve fibers and to modulate bronchial epithelium integrity and behavior. Current evidence suggest that BT downregulates epithelial mucins expression, cytokine production and metabolic profile. Despite these observations, biological mechanisms explaining asthma control improvement post-BT are still not well understood.
To assess whether BT affects gene signatures in bronchial epithelial cells (BECs).
In this study we evaluated the transcriptome of cultured bronchial epithelial cells (BECs) of severe asthmatics obtained pre- and post-BT treatment using microarrays. We further validated gene and protein expressions in BECs and in bronchial biopsies with immunohistochemistry pre- and post-BT treatment.
Transcriptomics analysis revealed that a large portion of differentially expressed genes (DEG) was involved in anti-viral response, anti-microbial response and pathogen induced cytokine storm signaling pathway. S100A gene family stood out as five members of this family where consistently downregulated post-BT. Further validation revealed that S100A7, S100A8, S100A9 and their receptor (RAGE, TLR4, CD36) expressions were highly enriched in severe asthmatic BECs. Further, these S100A family members were downregulated at the gene and protein levels in BECs and in bronchial biopsies of severe asthmatics post-BT. TLR4 and CD36 protein expression were also reduced in BECs post-BT. Thymic stromal lymphopoietin (TSLP) and human β-defensin 2 (hBD2) were significantly decreased while no significant change was observed in IL-25 and IL-33.
These data suggest that BT might improve asthma control by downregulating epithelial derived S100A family expression and related downstream signaling pathways.
重度哮喘影响一小部分哮喘患者，但代表了重大的医疗保健挑战。支气管热成形术（BT）是一种介入治疗方法，在考虑生物制剂治疗后，用于治疗未控制的重度哮喘。研究表明，BT 可以长期改善哮喘控制。这些改善似乎与 BT 降低气道平滑肌重塑、减少神经纤维数量以及调节支气管上皮完整性和功能的能力有关。目前的证据表明，BT 下调上皮粘蛋白的表达、细胞因子的产生和代谢特征。尽管有这些观察结果，但 BT 后改善哮喘控制的生物学机制仍未得到很好的理解。
评估 BT 是否影响支气管上皮细胞（BEC）中的基因特征。
在这项研究中，我们使用微阵列评估了严重哮喘患者支气管上皮细胞（BEC）在 BT 治疗前后的转录组。我们进一步通过 BT 治疗前后的免疫组织化学验证了 BEC 和支气管活检中的基因和蛋白表达。
转录组学分析显示，大量差异表达基因（DEG）参与抗病毒反应、抗微生物反应和病原体诱导的细胞因子风暴信号通路。S100A 基因家族作为该家族的五个成员脱颖而出，BT 治疗后这些基因一致下调。进一步验证显示，S100A7、S100A8、S100A9 及其受体（RAGE、TLR4、CD36）在严重哮喘患者的 BEC 中表达丰富。此外，BT 后 S100A 家族成员在 BEC 和严重哮喘患者的支气管活检中的基因和蛋白水平均下调。BT 后 BEC 中的 TLR4 和 CD36 蛋白表达也减少。胸腺基质淋巴细胞生成素（TSLP）和人β防御素 2（hBD2）显著下降，而 IL-25 和 IL-33 无明显变化。
这些数据表明，BT 可能通过下调上皮衍生的 S100A 家族表达和相关下游信号通路来改善哮喘控制。
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