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）中肺微血管内皮细胞功能障碍的意义之前，我们阐明了遗传多态性与COPD患者急性加重的关联。慢性阻塞性肺疾病（AECOPD）急性加重是慢性阻塞性肺疾病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症趋化因子基因的单核苷酸多态性（snp）在AECOPD气道中表达增强。方法：我们对276例男性COPD患者进行回顾性和前瞻性研究，研究了CCL11、CCL1和CCL5基因中与AECOPD发生频率和严重程度相关的4个snp。测量和主要结果：在为期两年的回顾性研究中，一个SNP （NCBI SNP参考：rs2282691）位于预测增强子区域，在显性模型中，CCL1基因编码一系列白细胞，包括单核细胞/巨噬细胞的趋化因子，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30个月的前瞻性研究中，“A”等位基因是AECOPD严重程度的显著危险等位基因，基因剂量效应明显[Kaplan-Meier法log-rank检验；AA vs. TT；log-rank统计量：7.67，P=0.006。Cox比例风险回归法；或：5.93 (1.28-27.48),p =0.023]。电迁移转移实验表明，C/EBPβ是肺部感染应答的关键转录因子，它与T等位基因结合，而不是与a等位基因结合。结论：CCL1基因变异与AECOPD易感性相关，可能与宿主抗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