Department of Clinical and Experimental Medicine, University of Birmingham Edgbaston, Birmingham, UK B15 2TT.
Am J Respir Crit Care Med. 2010 Jul 15;182(2):192-9. doi: 10.1164/rccm.200912-1846OC. Epub 2010 Mar 18.
Chronic obstructive pulmonary disease (COPD) has a genetic component, explaining susceptibility. Tumor necrosis factor (TNF)-alpha polymorphisms have been associated with COPD, but it is unclear if genotype influences clinical phenotype, protein expression, and bioactivity.
To determine if a functional polymorphism was important by assessing TNF-alpha expression and activity and its association with clinical severity over time.
Patients with COPD with rs361525 polymorphism were matched to patients with COPD without rs361525 polymorphism. TNF-alpha, its antagonists, and downstream mediators were measured in plasma and sputum. To determine TNF-alpha bioactivity, IL-8 secretion from primary bronchial epithelial cells (PBECs) was measured, and neutrophil migration was assessed using sputum from both subject groups in the presence and absence of TNF-alpha antibody. Subjects were followed annually and compared.
Patients with polymorphism had more chronic bronchitis, a lower body mass index, and a greater annual decline in FEV(1) than patients with COPD without rs361525 polymorphism. TNF-alpha concentrations were 100-fold higher in airway secretions from the patients with the rs361525 polymorphism, with no difference in TNF-alpha antagonists. Their lung secretions contained more IL-8 and myeloperoxidase, consistent with downstream inflammation. Sputum from patients with rs361525 polymorphism induced greater secretion of IL-8 from PBECs and increased neutrophil migration. These effects could be abrogated by TNF-alpha antibody, demonstrating the bioactivity of TNF-alpha in lung secretions from this group.
This TNF-alpha polymorphism is associated with clinical features of disease including progression. There is clear evidence of TNF-alpha overexpression and bioactivity with neutrophilic inflammation. The polymorphism is likely to be a factor that influences a COPD disease phenotype and its progression.
慢性阻塞性肺疾病（COPD）具有遗传成分，可解释其易感性。肿瘤坏死因子（TNF）-α多态性与 COPD 相关，但基因型是否影响临床表型、蛋白表达和生物活性尚不清楚。
通过评估 TNF-α的表达和活性及其与随时间推移的临床严重程度的相关性，确定功能性多态性是否重要。
将携带 rs361525 多态性的 COPD 患者与不携带 rs361525 多态性的 COPD 患者相匹配。在血浆和痰液中测量 TNF-α、其拮抗剂和下游介质。为了确定 TNF-α的生物活性，测量了原代支气管上皮细胞（PBEC）的 IL-8 分泌，并在存在和不存在 TNF-α抗体的情况下，使用来自两组受试者的痰液评估中性粒细胞迁移。对受试者进行每年随访并进行比较。
携带多态性的患者比不携带 rs361525 多态性的 COPD 患者有更多的慢性支气管炎、更低的体重指数和更大的 FEV1 年下降率。携带 rs361525 多态性的患者气道分泌物中的 TNF-α浓度高 100 倍，但 TNF-α拮抗剂无差异。他们的肺部分泌物含有更多的 IL-8 和髓过氧化物酶，与下游炎症一致。来自携带 rs361525 多态性的患者的痰液诱导 PBEC 分泌更多的 IL-8，并增加中性粒细胞迁移。这些作用可被 TNF-α抗体阻断，证明该组肺分泌物中 TNF-α的生物活性。
这种 TNF-α多态性与疾病的临床特征有关，包括进展。有明确的证据表明 TNF-α过度表达和生物活性伴有中性粒细胞炎症。该多态性可能是影响 COPD 疾病表型及其进展的因素之一。
