中性粒细胞型哮喘患者的气道炎症与小气道重构分析

Airway inflammation and small airway wall remodeling in neutrophilic asthma

目的:研究支气管哮喘(哮喘)患者的气道炎症表型分布,分析中性粒细胞哮喘表型的炎症标志物和临床特征,以及肺小血管和小气道重构指标。方法:采用横断面研究方法,选择北京大学第三医院呼吸内科2015年1月至12月完成诱导痰细胞学检查的患者63例,收集一般资料,记录哮喘控制测试(ACT)结果和肺功能,分析患者的诱导痰细胞计数及分类、诱导痰活化基质金属蛋白酶(matrix metalloproteinase-9,MMP-9)水平,血清瘦素、Ig E、骨膜素及TGF-β1水平,分析肺CT肺小血管横截面积及小气道横截面积。结果:哮喘患者的气道炎症表型分布为嗜酸粒细胞型22例(34.9%),中性粒细胞型22例(34.9%),混合细胞型15例(23.8%),寡细胞型4例(6.3%)。中性粒细胞型哮喘与嗜酸性粒细胞型相比,痰活化MMP-9水平显著增高[179.1(74.3,395.5)vs.50.5(9.7,225.8),P<0.05]。痰中性粒细胞计数与第一秒用力呼气量占预测值百分比(predicted percentage of forced expiratory volume in the 1st second,FEV1%pred)呈显著负相关(r=-0.304,P<0.05),与痰活化MMP-9水平成显著正相关(r=0.469,P<0.05),与小气道校正壁厚呈相关趋势(r=0.533,P=0.06)。痰活化MMP-9水平与FEV1%pred呈负相关(r=-0.281,P<0.05),与小气道校正壁厚呈相关趋势(r=0.612,P=0.06),与校正管径面积呈正相关(r=0.636,P<0.05)。外周血中性粒细胞计数与痰中性粒细胞计数呈正相关(r=0.355,P<0.05),与痰MMP-9水平呈正相关(r=0.330,P<0.05)。结论:哮喘患者气道中性粒细胞数量与肺功能相关,中性粒细胞可能通过释放MMP-9加重小气道重构;痰中性粒细胞计数与外周血中性粒细胞计数相关,有可能作为判断炎症亚型的替代物。

Objective： To investigate the distribution of airway inflammation phenotype in patients with bronchial asthma（asthma）,and to analyze clinical characteristics,inflammatory cytokines,pulmonary small vessels remodeling and small airway wall remodeling in patients with neutrophilic asthma. Methods： Sixty-three patients with asthma were enrolled from January 2015 to December 2015 in Peking University Third Hospital. Clinical data including gender,age,body mass index（BMI）,pulmonary function tests（PFTs）,asthma control test（ACT） were recorded. All the patients underwent sputum induction.The cellular composition of the sputum was evaluatedand the concentration of active MMP-9 in the sputum tested. Blood routine tests were done and the concentration of Ig E,periostin,and TGF-beta1 levels were measured in serum by enzyme-linked immunosorbent assay（ELISA）. Small airway wall remodeling was measured in computed tomography（CT） scans,as the luminal diameter,luminal area,wall thickness and wall area % adjusted by body surface area（BSA） at the end of the 6 th generation airway,in which the inner diameter was less than 2 mm. Small vascular alterations were measured by cross-sectional area（CSA）,and the total vessel CSA 5 mm2 was calculated using imaging software. Results： The distributions of airway inflammatory phenotypes of the asthmatic patients were as follows： neutrophilic asthma（34. 9%,22/63）,eosinophilic asthma（34. 9%,22/63）,mixed granulocytic asthma（23. 8%,15/63）,and paucigranulocytic asthma（6. 3%,4/63）. The neutrophilic subtype patients had a significantly higher active MMP-9 level in sputum compared with the eosinophilic phenotypepatuents,as 179. 1（74. 3,395. 5） vs. 50. 5（9. 7,225. 8）,P〈0. 05. Sputum neutrophil count was negatively correlated with FEV1% pred（r =-0. 304,P〈0. 05）,and positively correlated with active MMP-9 level in sputum（r =-0. 304,P〈0. 05）,and positive correlation trend with airway wall thickness（r = 0. 533,P =0. 06）. There was a significantly negative correlation of active MMP-9 level in sputum with FEV1% pred（r =-0. 281,P〈0. 05）,in positive correlation with small airway wall area（%）（r = 0. 612,P〈0. 05）,and inpositive correlation trend with airway wall thickness（r = 0. 612,P = 0. 06）. Neutrophils count in peripheral blood was positively correlated with neutrophil counts in sputum. Conclusion： Neutrophil count in airway is related to lung function in asthmatic patients. Neutrophils may accelerate small airway wall remodeling through the release of active MMP-9. Neutrophil count in peripheral blood is related to neutrophils count in sputum,which may be used as a substitute for evaluating inflammatory phenotype.