Shi Jun, Tang Jiajia, Liu Lu, Zhang Chunyang, Chen Wei, Qi Man, Han Zhihai, Chen Xuxin
School of Medicine, South China University of Technology, Guangzhou, 510006, China.
Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China.
Mol Biotechnol. 2025 Apr;67(4):1565-1583. doi: 10.1007/s12033-024-01141-6. Epub 2024 Apr 24.
Acute respiratory distress syndrome (ARDS), a progressive status of acute lung injury (ALI), is primarily caused by an immune-mediated inflammatory disorder, which can be an acute pulmonary complication of rheumatoid arthritis (RA). As a chronic inflammatory disease regulated by the immune system, RA is closely associated with the occurrence and progression of respiratory diseases. However, it remains elusive whether there are shared genes between the molecular mechanisms underlying RA and ARDS. The objective of this study is to identify potential shared genes for further clinical drug discovery through integrated analysis of bulk RNA sequencing datasets obtained from the Gene Expression Omnibus database, employing differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA). The hub genes were identified through the intersection of common DEGs and WGCNA-derived genes. The Random Forest (RF) and least absolute shrinkage and selection operator (LASSO) algorithms were subsequently employed to identify key shared target genes associated with two diseases. Additionally, RA immune infiltration analysis and COVID-19 single-cell transcriptome analysis revealed the correlation between these key genes and immune cells. A total of 59 shared genes were identified from the intersection of DEGs and gene clusters obtained through WGCNA, which analyzed the integrated gene matrix of ALI/ARDS and RA. The RF and LASSO algorithms were employed to screen for target genes specific to ALI/ARDS and RA, respectively. The final set of overlapping genes (FCMR, ADAM28, HK3, GRB10, UBE2J1, HPSE, DDX24, BATF, and CST7) all exhibited a strong predictive effect with an area under the curve (AUC) value greater than 0.8. Then, the immune infiltration analysis revealed a strong correlation between UBE2J1 and plasma cells in RA. Furthermore, scRNA-seq analysis demonstrated differential expression of these nine target genes primarily in T cells and NK cells, with CST7 showing a significant positive correlation specifically with NK cells. Beyond that, transcriptome sequencing was conducted on lung tissue collected from ALI mice, confirming the substantial differential expression of FCMR, HK3, UBE2J1, and BATF. This study provides unprecedented evidence linking the pathophysiological mechanisms of ALI/ARDS and RA to immune regulation, which offers novel understanding for future clinical treatment and experimental research.
急性呼吸窘迫综合征（ARDS）是急性肺损伤（ALI）的一种进展状态，主要由免疫介导的炎症紊乱引起，它可能是类风湿关节炎（RA）的一种急性肺部并发症。作为一种受免疫系统调节的慢性炎症性疾病，RA与呼吸系统疾病的发生和发展密切相关。然而，RA和ARDS潜在的分子机制之间是否存在共同基因仍不清楚。本研究的目的是通过对从基因表达综合数据库获得的批量RNA测序数据集进行综合分析，采用差异表达基因（DEG）分析和加权基因共表达网络分析（WGCNA），来识别潜在的共同基因，以便进一步进行临床药物研发。通过共同DEG和WGCNA衍生基因的交集确定了枢纽基因。随后采用随机森林（RF）和最小绝对收缩和选择算子（LASSO）算法来识别与这两种疾病相关的关键共同靶基因。此外，RA免疫浸润分析和COVID-19单细胞转录组分析揭示了这些关键基因与免疫细胞之间的相关性。通过对ALI/ARDS和RA的综合基因矩阵进行WGCNA分析，从DEG和基因簇的交集中共鉴定出59个共同基因。分别采用RF和LASSO算法筛选ALI/ARDS和RA特有的靶基因。最终的重叠基因集（FCMR、ADAM28、HK3、GRB10、UBE2J1、HPSE、DDX24、BATF和CST7）的曲线下面积（AUC）值均大于0.8，均表现出较强的预测效果。然后，免疫浸润分析显示RA中UBE2J1与浆细胞之间存在很强的相关性。此外，单细胞RNA测序（scRNA-seq）分析表明，这九个靶基因主要在T细胞和自然杀伤（NK）细胞中差异表达，其中CST7与NK细胞呈显著正相关。除此之外，对从ALI小鼠收集的肺组织进行了转录组测序，证实了FCMR、HK3、UBE2J1和BATF存在大量差异表达。本研究提供了将ALI/ARDS和RA的病理生理机制与免疫调节联系起来的前所未有的证据，为未来的临床治疗和实验研究提供了新的认识。
