Perez-Pons Manel, Molinero Marta, Benítez Iván D, García-Hidalgo María C, Chatterjee Shambhabi, Bär Christian, González Jessica, Torres Antoni, Barbé Ferran, de Gonzalo-Calvo David
Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain.
CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain.
Mol Ther Nucleic Acids. 2024 Jan 10;35(1):102118. doi: 10.1016/j.omtn.2024.102118. eCollection 2024 Mar 12.
Elucidating the pathobiological mechanisms underlying post-acute pulmonary sequelae following SARS-CoV-2 infection is essential for early interventions and patient stratification. Here, we investigated the potential of microRNAs (miRNAs) as theranostic agents for pulmoprotection in critical illness survivors. Multicenter study including 172 ICU survivors. Diffusion impairment was defined as a lung-diffusing capacity for carbon monoxide (D) <80% within 12 months postdischarge. A disease-associated 16-miRNA panel was quantified in plasma samples collected at ICU admission. Bioinformatic analyses were conducted using KEGG, Reactome, GTEx, and Drug-Gene Interaction databases. The results were validated using an external RNA-seq dataset. A 3-miRNA signature linked to diffusion impairment (miR-27a-3p, miR-93-5p, and miR-199a-5p) was identified using random forest. Levels of miR-93-5p and miR-199a-5p were independently associated with the outcome, improving patient classification provided by the electronic health record. The experimentally validated targets of these miRNAs exhibited enrichment across diverse pathways, with telomere length quantification in an additional set of samples (n = 83) supporting the role of cell senescence in sequelae. Analysis of an external dataset refined the pathobiological fingerprint of pulmonary sequelae. Gene-drug interaction analysis revealed four FDA-approved drugs. Overall, this study advances our understanding of lung recovery in postacute respiratory infections, highlighting the potential of miRNAs and their targets for pulmoprotection.
阐明新型冠状病毒2感染后急性肺后遗症的病理生物学机制对于早期干预和患者分层至关重要。在此，我们研究了微小RNA（miRNA）作为危重症幸存者肺保护治疗诊断剂的潜力。这项多中心研究纳入了172名重症监护病房幸存者。弥散障碍定义为出院后12个月内一氧化碳肺弥散量（D）<80%。在重症监护病房入院时采集的血浆样本中对一个与疾病相关的16-miRNA组进行定量分析。使用KEGG、Reactome、GTEx和药物-基因相互作用数据库进行生物信息学分析。结果使用外部RNA测序数据集进行验证。使用随机森林识别出一个与弥散障碍相关的3-miRNA特征（miR-27a-3p、miR-93-5p和miR-199a-5p）。miR-93-5p和miR-199a-5p的水平与预后独立相关，改善了电子健康记录提供的患者分类。这些miRNA经实验验证的靶标在多种途径中表现出富集，在另一组样本（n = 83）中进行的端粒长度定量分析支持细胞衰老在后遗症中的作用。对外部数据集的分析完善了肺后遗症的病理生物学特征。基因-药物相互作用分析揭示了四种美国食品药品监督管理局批准的药物。总体而言，本研究增进了我们对急性呼吸感染后肺恢复的理解，突出了miRNA及其靶标在肺保护方面的潜力。
