Priority Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia.
Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia.
Respir Res. 2023 Jan 25;24(1):32. doi: 10.1186/s12931-022-02298-x.
Lung transcriptomics studies in asthma have provided valuable information in the whole lung context, however, deciphering the individual contributions of the airway and parenchyma in disease pathogenesis may expedite the development of novel targeted treatment strategies. In this study, we performed transcriptomics on the airway and parenchyma using a house dust mite (HDM)-induced model of experimental asthma that replicates key features of the human disease. HDM exposure increased the expression of 3,255 genes, of which 212 were uniquely increased in the airways, 856 uniquely increased in the parenchyma, and 2187 commonly increased in both compartments. Further interrogation of these genes using a combination of network and transcription factor enrichment analyses identified several transcription factors that regulate airway and/or parenchymal gene expression, including transcription factor EC (TFEC), transcription factor PU.1 (SPI1), H2.0-like homeobox (HLX), metal response element binding transcription factor-1 (MTF1) and E74-like factor 4 (ets domain transcription factor, ELF4) involved in controlling innate immune responses. We next assessed the effects of inhibiting lung SPI1 responses using commercially available DB1976 and DB2313 on key disease outcomes. We found that both compounds had no protective effects on airway inflammation, however DB2313 (8 mg/kg) decreased mucus secreting cell number, and both DB2313 (1 mg/kg) and DB1976 (2.5 mg/kg and 1 mg/kg) reduced small airway collagen deposition. Significantly, both compounds decreased airway hyperresponsiveness. This study demonstrates that SPI1 is important in HDM-induced experimental asthma and that its pharmacological inhibition reduces HDM-induced airway collagen deposition and hyperresponsiveness.
哮喘的肺转录组学研究在全肺背景下提供了有价值的信息，然而，解析气道和实质在疾病发病机制中的个体贡献可能会加速新的靶向治疗策略的发展。在这项研究中，我们使用尘螨（HDM）诱导的实验性哮喘模型对气道和实质进行了转录组学研究，该模型复制了人类疾病的关键特征。HDM 暴露增加了 3255 个基因的表达，其中 212 个在气道中特异性增加，856 个在实质中特异性增加，2187 个在两个隔室中共同增加。使用网络和转录因子富集分析的组合进一步研究这些基因，确定了几个调节气道和/或实质基因表达的转录因子，包括转录因子 EC（TFEC）、转录因子 PU.1（SPI1）、H2.0 样同源盒（HLX）、金属反应元件结合转录因子-1（MTF1）和 E74 样因子 4（ets 域转录因子，ELF4），它们参与控制先天免疫反应。我们接下来评估了使用商业上可获得的 DB1976 和 DB2313 抑制肺 SPI1 反应对关键疾病结局的影响。我们发现，这两种化合物对气道炎症均无保护作用，但是 DB2313（8mg/kg）减少了黏液分泌细胞的数量，DB2313（1mg/kg）和 DB1976（2.5mg/kg 和 1mg/kg）均减少了小气道胶原沉积。重要的是，这两种化合物均降低了气道高反应性。这项研究表明，SPI1 在 HDM 诱导的实验性哮喘中很重要，其药理抑制可减少 HDM 诱导的气道胶原沉积和气道高反应性。
