Sonic hedgehog signalling as a potential endobronchial biomarker in COPD
Sonic hedgehog signalling as a potential endobronchial biomarker in COPD
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Sonic hedgehog信号作为COPD潜在的支气管内生物标志物
DOI：
10.1186/s12931-020-01478-x
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发表时间：
2020-08-07
影响因子：
5.8
通讯作者：
Dormoy, Valerian
中科院分区：
文献类型：
--
作者：
Ancel, Julien;Belgacemi, Randa;Dormoy, Valerian
背景在全基因组关联研究中，hedgehog（HH）通路与慢性阻塞性肺疾病（COPD）相关，最近的研究表明HH信号传导在COPD中可能发生改变。因此，我们使用微创支气管内手术来评估HH通路的激活，包括主要转录因子Gli 2和配体Sonic HH（Shh）。方法选择非COPD患者30例，COPD患者28例。通过纤维支气管镜检查获得支气管刷检、支气管肺泡灌洗液（BALF）和支气管活检。通过免疫染色评价细胞群和亚细胞定位的表征。进行ELISA和RNAseq分析以鉴定来自非COPD和COPD患者的BAL中的Shh蛋白和肺组织上的转录物，并在外部和独立队列中进行验证。结果与非COPD患者相比，COPD患者在支气管刷检中表现出更大比例的基底细胞（26 +/- 11% vs 13 +/- 6%;p < 0.0001）。在支气管刷检和活检中，COPD受试者的气道基底细胞呈现较低强度的Gli 2核染色（p < 0.05）。来自COPD患者的支气管BALF含有比非COPD BALF更低的Shh浓度（12.5 vs 40.9 pg/mL;p = 0.002）;在验证队列中COPD肺中的SHH转录物也减少（p = 0.0001）。结论本研究证实了通过支气管镜采集的呼吸道样本中评估HH通路激活的可行性，并确定了COPD患者支气管上皮HH信号转导受损。
Background The hedgehog (HH) pathway has been associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies and recent studies suggest that HH signalling could be altered in COPD. We therefore used minimally invasive endobronchial procedures to assess activation of the HH pathway including the main transcription factor, Gli2, and the ligand, Sonic HH (Shh). Methods Thirty non-COPD patients and 28 COPD patients were included. Bronchial brushings, bronchoalveolar lavage fluid (BALF) and bronchial biopsies were obtained from fiberoptic bronchoscopy. Characterization of cell populations and subcellular localization were evaluated by immunostaining. ELISA and RNAseq analysis were performed to identify Shh proteins in BAL and transcripts on lung tissues from non-COPD and COPD patients with validation in an external and independent cohort. Results Compared to non-COPD patients, COPD patients exhibited a larger proportion of basal cells in bronchial brushings (26 +/- 11% vs 13 +/- 6%;p < 0.0001). Airway basal cells of COPD subjects presented less intense nuclear staining for Gli2 in bronchial brushings and biopsies (p < 0.05). Bronchial BALF from COPD patients contained lower Shh concentrations than non-COPD BALF (12.5 vs 40.9 pg/mL;p = 0.002); SHH transcripts were also reduced in COPD lungs in the validation cohort (p = 0.0001). Conclusion This study demonstrates the feasibility of assessing HH pathway activation in respiratory samples collected by bronchoscopy and identifies impaired bronchial epithelial HH signalling in COPD.