Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan.
Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan.
Chest. 2017 Jul;152(1):58-69. doi: 10.1016/j.chest.2017.03.012. Epub 2017 Mar 15.
The p53 signaling pathway may be important for the pathogenesis of emphysematous changes in the lungs of smokers. Polymorphism of p53 at codon 72 is known to affect apoptotic effector proteins, and the polymorphism of mouse double minute 2 homolog (MDM2) single nucleotide polymorphism (SNP)309 is known to increase MDM2 expression. The aim of this study was to assess polymorphisms of the p53 and MDM2 genes in smokers and confirm the role of SNPs in these genes in the pathogenesis of pulmonary emphysema.
This study included 365 patients with a smoking history, and the polymorphisms of p53 and MDM2 genes were identified. The degree of pulmonary emphysema was determined by means of CT scanning. SNPs, MDM2 mRNA, and p53 protein levels were assessed in human lung tissues from smokers. Plasmids encoding p53 and MDM2 SNPs were used to transfect human lung fibroblasts (HLFs) with or without cigarette smoke extract (CSE), and the effects on cell proliferation and MDM2 promoter activity were measured.
The polymorphisms of the p53 and MDM2 genes were associated with emphysematous changes in the lung and were also associated with p53 protein and MDM2 mRNA expression in the lung tissue samples. Transfection with a p53 gene-coding plasmid regulated HLF proliferation, and the analysis of P2 promoter activity in MDM2 SNP309-coding HLFs showed the promoter activity was altered by CSE.
Our data demonstrated that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in lungs from smokers.
p53 信号通路可能对吸烟者肺部气肿变化的发病机制很重要。p53 密码子 72 点的多态性已知会影响凋亡效应蛋白，而鼠双微体 2 同源物（MDM2）单核苷酸多态性（SNP）309 的多态性已知会增加 MDM2 的表达。本研究旨在评估吸烟人群中 p53 和 MDM2 基因的多态性，并证实这些基因中的 SNP 在肺肺气肿发病机制中的作用。
本研究纳入了 365 名有吸烟史的患者，鉴定了 p53 和 MDM2 基因的多态性。通过 CT 扫描确定肺气肿的程度。评估了吸烟者肺组织中的 SNPs、MDM2 mRNA 和 p53 蛋白水平。用编码 p53 和 MDM2 SNP 的质粒转染人肺成纤维细胞（HLFs），并加入或不加入香烟烟雾提取物（CSE），检测对细胞增殖和 MDM2 启动子活性的影响。
p53 和 MDM2 基因的多态性与肺部气肿变化有关，也与肺组织样本中的 p53 蛋白和 MDM2 mRNA 表达有关。转染编码 p53 基因的质粒可调节 HLF 的增殖，而分析 MDM2 SNP309 编码的 HLFs 中的 P2 启动子活性表明，CSE 改变了启动子活性。
我们的数据表明，p53 和 MDM2 基因多态性与凋亡信号和吸烟相关的肺气肿变化有关。
