Zheng Xiang-Yun, Huang Heng, Wei Zhen-Ting, Yan Hao-Ji, Wang Xiao-Wen, Xu Lin, Li Cai-Han, Tang Hong-Tao, Wang Jun-Jie, Yu Zeng-Wei, Tian Dong
Heart and Lung Transplant Research Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China.
Heart and Lung Transplant Research Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China.
Transpl Immunol. 2022 Apr;71:101556. doi: 10.1016/j.trim.2022.101556. Epub 2022 Feb 22.
The unclear mechanism that ischemia-reperfusion injury (IRI) contributes to the development of primary graft dysfunction (PGD) and chronic lung allograft dysfunction (CLAD) remains a major issue in lung transplantation. Differentially expressed PGD-related genes and CLAD-related genes during IRI (IRI-PGD common genes and IRI-CLAD common genes) were identified using GEO datasets (GSE127003, GSE8021, GSE9102) and GeneCards datasets. Enrichment analysis and four network analyses, namely, protein-protein interaction, microRNA (miRNA)-gene, transcription factor (TF)-gene, and drug-gene networks, were then performed. Moreover, GSE161520 was analyzed to identify the differentially expressed core miRNAs during IRI in rats. Finally, Pearson correlation analysis and ROC analysis were performed. Eight IRI-PGD common genes (IL6, TNF, IL1A, IL1B, CSF3, CXCL8, SERPINE1, and PADI4) and 10 IRI-CLAD common genes (IL1A, ICAM1, CCL20, CCL2, IL1B, TNF, PADI4, CXCL8, GZMB, and IL6) were identified. Enrichment analysis showed that both IRI-PGD and IRI-CLAD common genes were significantly enriched in "AGE-RAGE signaling pathway in diabetic complication" and "IL-17 signaling pathway". Among the core miRNAs, miR-1-3p and miR-335 were differentially expressed in IRI rats. Among core TFs, CEBPB expression had a significant negative correlation with P/F ratio (r = -0.33, P = 0.021). In the reperfused lung allografts, the strongest positive correlation was exhibited between PADI4 expression and neutrophil proportion (r = 0.76, P < 0.001), and the strongest negative correlation was between PADI4 expression and M2 macrophage proportion (r = -0.74, P < 0.001). In lung allografts of PGD recipients, IL6 expression correlated with activated dendritic cells proportion (r = 0.86, P < 0.01), and IL1B expression correlated with the neutrophils proportion(r = 0.84, P < 0.01). In whole blood of CLAD recipients, GZMB expression correlated with activated CD4+ memory T cells proportion (r = 0.76, P < 0.001).Our study provides the novel insights into the molecular mechanisms by which IRI contributes to PGD and CLAD and potential targets for therapeutic intervention.
缺血再灌注损伤（IRI）导致原发性移植肺功能障碍（PGD）和慢性移植肺功能障碍（CLAD）的机制尚不清楚，这仍然是肺移植中的一个主要问题。利用基因表达综合数据库（GEO数据集，即GSE127003、GSE8021、GSE9102）和基因卡片数据集，确定了IRI期间差异表达的PGD相关基因和CLAD相关基因（IRI-PGD共同基因和IRI-CLAD共同基因）。然后进行了富集分析和四种网络分析，即蛋白质-蛋白质相互作用、微小RNA（miRNA）-基因、转录因子（TF）-基因和药物-基因网络分析。此外，对GSE161520进行分析，以确定大鼠IRI期间差异表达的核心miRNA。最后进行了Pearson相关性分析和ROC分析。确定了8个IRI-PGD共同基因（IL6、TNF、IL1A、IL1B、CSF3、CXCL8、SERPINE1和PADI4）和10个IRI-CLAD共同基因（IL1A、ICAM1、CCL20、CCL2、IL1B、TNF、PADI4、CXCL8、GZMB和IL6）。富集分析表明，IRI-PGD和IRI-CLAD共同基因均显著富集于“糖尿病并发症中的AGE-RAGE信号通路”和“IL-17信号通路”。在核心miRNA中，miR-1-3p和miR-335在IRI大鼠中差异表达。在核心TF中，CEBPB表达与P/F比值呈显著负相关（r = -0.33，P = 0.021）。在再灌注的移植肺中，PADI4表达与中性粒细胞比例之间呈现最强的正相关（r = 0.76，P < 0.001），而PADI4表达与M2巨噬细胞比例之间呈现最强的负相关（r = -0.74，P < 0.001）。在PGD受者的移植肺中，IL6表达与活化树突状细胞比例相关（r = 0.86，P < 0.01），IL1B表达与中性粒细胞比例相关（r = 0.84，P < 0.01）。在CLAD受者的全血中，GZMB表达与活化的CD4+记忆T细胞比例相关（r = 0.76，P < 0.001）。我们的研究为IRI导致PGD和CLAD的分子机制以及治疗干预的潜在靶点提供了新的见解。
