Relationship between serum TLR3 mRNA levels and acute exacerbation in patients with chronic obstructive pulmonary disease
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摘要: 目的 分析慢性阻塞性肺疾病(chronic obstructive pulmonary disease，COPD)患者血清Toll样受体3(toll-like receptor 3，TLR3)信使RNA(messenger RNA，mRNA)水平与急性加重期发生的关系。方法 选择2021年11月—2022年10月儋州市人民医院收治的COPD急性加重期患者50例作为COPD急性加重期组、COPD稳定期患者52例作为COPD稳定期组、体检健康者55例作为对照组。收集所有受试者临床资料、肺功能指标[第1秒用力呼气容积占预计值百分比(FEV1%)、第1秒用力呼气容积与用力肺活量的比值(FEV1/FVC)]；酶联免疫吸附法检测受试者血清白细胞介素-4(IL-4)、肿瘤坏死因子-α(TNF-α)、超敏C反应蛋白(hs-CRP)水平；荧光定量PCR法检测受试者血清TLR3 mRNA水平；Pearson法或Spearman法分析COPD急性加重期患者血清TLR3 mRNA水平与吸烟史、FEV1%、FEV1/FVC、IL-4、TNF-α、hs-CRP水平的相关性；多因素logistic回归分析影响COPD患者急性加重期发生的独立危险因素；受试者工作特征曲线分析血清TLR3 mRNA水平对COPD患者急性加重期发生的预测价值。结果 对照组、COPD稳定期组、COPD急性加重期组吸烟史比例、血清IL-4、TNF-α、hs-CRP、TLR3 mRNA水平依次升高(P < 0.05)，FEV1%、FEV1/FVC水平依次降低(P < 0.05)；COPD急性加重期患者血清TLR3 mRNA水平与吸烟史、IL-4、TNF-α、hs-CRP水平呈正相关(P < 0.05)，与FEV1%、FEV1/FVC水平呈负相关(P < 0.05)；有吸烟史、血清IL-4、TNF-α、hs-CRP、TLR3 mRNA水平高、FEV1%、FEV1/FVC水平低是影响COPD患者急性加重期发生的独立危险因素(P < 0.05)；血清TLR3 mRNA水平预测COPD患者急性加重期发生的曲线下面积为0.862，截断值为1.82，特异度为68.8%，灵敏度为91.7%。结论 COPD患者血清TLR3 mRNA呈高表达，监测其水平变化有利于预测COPD患者急性加重期的发生。Abstract: Objective To analyze the relationship between serum toll-like receptor 3(TLR3) messenger RNA(mRNA) levels and acute exacerbation in patients with chronic obstructive pulmonary disease(COPD).Methods Fifty patients with COPD acute exacerbation treated in Danzhou People's Hospital from November 2021 to October 2022 were selected as COPD acute exacerbation group, 52 patients with COPD stable phase as COPD stable phase group, and 55 healthy patients with physical examination as control group. Clinical data and pulmonary function indicators(percentage of forced expiratory volume of 1 s to expected value[FEV1%], ratio of forced expiratory volume of 1 s to forced vital capacity[FEV1/FVC]) of all subjects were collected. Serum levels of interleukin-4(IL-4), tumor necrosis factor-α(TNF-α) and hypersensitive C-reactive protein(hs-CRP) were determined by enzyme linked immunosorbent assay. Serum TLR3 mRNA level was detected by fluorescence quantitative PCR. Pearson or Spearman method was used to analyze the correlation between serum TLR3 mRNA level and smoking history, FEV1%, FEV1/FVC, IL-4, TNF-α and hs-CRP levels in patients with acute exacerbation of COPD. Multivariate logistic regression analysis was used to analyze independent risk factors affecting the occurrence of acute exacerbation in COPD patients. The predictive value of serum TLR3 mRNA level in COPD patients with acute exacerbation was analyzed by receiver operating characteristic curve.Results The proportion of smoking history, serum IL-4, TNF-α, hs-CRP and TLR3 mRNA levels in control group, COPD stable group and COPD acute exacerbation group were increased successively(P < 0.05), while the levels of FEV1% and FEV1/FVC were decreased successively(P < 0.05). The serum level of TLR3 mRNA in patients with acute exacerbation of COPD was positively correlated with smoking history, levels of IL-4, TNF-α and hs-CRP(P < 0.05), and negatively correlated with FEV1% and FEV1/FVC(P < 0.05). Smoking history, high serum levels of IL-4, TNF-α, hs-CRP, TLR3 mRNA, low levels of FEV1% and FEV1/FVC were independent risk factors affecting the occurrence of acute exacerbation of COPD patients(P < 0.05). Serum TLR3 mRNA level predicted the occurrence of acute exacerbation in COPD patients with an area under the curve of 0.862, a cut-off value of 1.82, a specificity of 68.8%, and a sensitivity of 91.7%.Conclusion Serum TLR3 mRNA was highly expressed in COPD patients, and monitoring its level was beneficial to predict the occurrence of acute exacerbation in COPD patients.
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表 1 引物序列
基因名称 正向引物(5′-3′) 反向引物(5′-3′) TLR3 ATAAGAATGATGTGGCCTAC TAAGTCCATGGCACAAAGTG GAPDH GTCTACACTTGAGGGCACCA CCAGGTCAATCTAATGGGCT 
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表 2 对照组、COPD稳定期组、COPD急性加重期组临床资料、肺功能和炎症指标比较
X±S，例(%) 指标 对照组(n=55) COPD稳定期组(n=52) COPD急性加重期组(n=50) χ2/F P 性别 0.423 0.809 男 34(61.82) 29(55.77) 30(60.00) 女 21(38.18) 23(44.23) 20(40.00) 年龄/岁 57.56±7.52 56.27±7.96 58.46±8.28 0.989 0.374 BMI/(kg/m2) 23.72±2.61 24.27±2.49 24.13±2.15 0.742 0.478 吸烟史 26(47.27) 31(59.62)1) 37(74.00)1)2) 7.789 0.020 饮酒史 27(49.09) 28(53.85) 25(50.00) 0.269 0.874 FEV1%/% 92.27±7.07 67.26±10.651) 49.14±9.401)2) 296.951 < 0.001 FEV1/FVC/% 86.28±12.68 63.53±9.221) 41.57±7.481)2) 256.166 < 0.001 IL-4/(ng/L) 58.54±11.52 105.48±27.481) 215.65±41.751)2) 395.602 < 0.001 TNF-α/(ng/L) 15.82±1.69 28.58±2.251) 42.46±2.681)2) 1872.459 < 0.001 hs-CRP/(mg/L) 5.35±1.48 17.36±2.111) 29.44±2.861)2) 1569.553 < 0.001 与对照组比较，1)P < 0.05；与COPD稳定期组比较，2)P < 0.05。
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表 3 对照组、COPD稳定期组、COPD急性加重期组血清TLR3 mRNA水平的比较
X±S 组别 例数 TLR3 mRNA 对照组 55 1.00±0.00 COPD稳定期组 52 1.67±0.221) COPD急性加重期组 50 2.16±0.411)2) F 256.945 P < 0.001 与对照组比较，1)P < 0.05；与COPD稳定期组比较，2)P < 0.05。
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表 4 COPD急性加重期患者血清TLR3 mRNA水平与吸烟史、FEV1%、FEV1/FVC、IL-4、TNF-α、hs-CRP水平的相关性分析
指标 吸烟史 FEV1% FEV1/FVC IL-4 TNF-α hs-CRP TLR3 mRNA r 0.356 -0.412 -0.377 0.468 0.511 0.528 P 0.011 0.003 0.007 0.001 < 0.001 < 0.001
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表 5 影响COPD患者急性加重期发生的多因素logistic回归分析
影响因素 β SE Waldχ2 P OR 95%CI 吸烟史 0.720 0.269 7.164 0.007 2.054 1.213~3.481 FEV1% 0.589 0.257 5.252 0.022 1.802 1.089~2.982 FEV1/FVC 0.693 0.326 4.519 0.034 2.000 1.056~3.788 IL-4 0.439 0.104 17.818 < 0.001 1.551 1.265~1.902 TNF-α 0.478 0.214 4.989 0.026 1.613 1.060~2.453 hs-CRP 0.598 0.201 8.851 0.003 1.818 1.226~2.697 TLR3 mRNA 0.655 0.217 9.111 0.003 1.925 1.258~2.946
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