The significance of endothelial cell dysfunction in pulmonary microvessels in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis

在研究慢性阻塞性肺疾病（COPD）和特发性肺纤维化（IPF）肺微血管内皮细胞功能障碍的意义之前，我们阐明了COPD患者急性加重与基因多态性的相关性。慢性阻塞性肺疾病急性加重（AECOPD）是COPD发病率和死亡率的主要原因。目的：宿主防御机制的显著异质性可能归因于炎性趋化因子基因的单核苷酸多态性（SNP），这些基因在AECOPD气道中表现出增强的表达。研究方法：我们对276例男性COPD患者进行了回顾性和前瞻性研究，研究了CCL 11、CCL 1和CCL 5基因中4个SNP与AECOPD发生频率和严重程度的关系。测量和主要结果：在两年的回顾性研究中，预测的增强子区域中的一个SNP（NCBI SNP参考：rs 2282691）， ...更多信息 在显性模型中，编码一系列白细胞（包括单核细胞/巨噬细胞）的趋化因子的CCL 1基因与AECOPD的频率显著相关（Fisher精确检验[比值比（OR）（95%置信区间）：2.70（1.36-5.36），P=0.004]，logistic回归[OR：3.06（1.46-6.41），P=0.003]，Kruskal-Wallis检验（P=0.003）}。在为期30个月的前瞻性研究中，“A”等位基因是AECOPD严重程度的显著风险等位基因，具有明显的基因剂量效应[Kaplan-Meier法和对数秩检验; AA vs. TT ;对数秩统计量：7.67，P=0.006。考克斯比例风险回归法; OR：5.93（1.28-27.48），P=0.023]。电迁移率改变分析表明，C/EBPβ，一个关键的转录因子，在肺部感染的反应，结合'T'等位基因，但不结合'A'等位基因。结论：CCL 1基因的变异与AECOPD的易感性有关，可能与宿主对AECOPD防御机制的异质性有关。少

Prior to investigate the significance of endothelial cell dysfunction in pulmonary micro-vessels in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), we elucidated the association of genetic polymorphisms with acute exacerbations in patients with COPD. Acute exacerbations in chronic obstructive pulmonary disease (AECOPD) are a major cause of morbidity and mortality in COPD. Objectives : The marked heterogeneity in the host defense mechanisms may be attributed to the single nucleotide polymorphisms (SNPs) in the inflammatory chemokine genes that show enhanced expressions in the airway of AECOPD. Methods : We have investigated four SNPs in CCL11, CCL1, and CCL5 genes with relation to the frequency and severity of AECOPD in the retrospective and prospective study of a cohort of 276 male patients with COPD. Measurements and Main Results : In the retrospective study for two years, one SNP (NCBI SNP reference : rs2282691) in the predicted enhancer region o … More f CCL1 gene, encoding a chemotactic factor for a series of leukocytes, including monocytes/macrophages, was significantly associated with the frequency of AECOPD in a dominant model {Fisher's exact test [odds ratio (OR) (95% confidence interval) : 2.70 (1.36-5.36), P=0.004], logistic regression [OR : 3.06 (1.46-6.41), P=0.003], and Kruskal-Wallis test (P=0.003)}. In the prospective study for 30 months, the 'A' allele was a significant risk allele for the severity of AECOPD with obvious gene dosage effect [Kaplan-Meier method with log-rank test ; AA vs. TT ; log-rank statistic : 7.67, P=0.006. Cox proportional hazards regression method ; OR : 5.93 (1.28-27.48), P=0.023]. The electromobility shift assay showed that C/EBPβ, a key transcriptional factor in response to pulmonary infections, binds to the 'T' allele, but not to the 'A' allele. Conclusions : Variants in CCL1 gene are associated with susceptibility to AECOPD through their potential implication in the heterogeneous features of the host defense mechanisms against AECOPD. Less