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6...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。展开更多
OBJECTIVE Airway wall remodeling(AWR),which refers to structural changes in the airway,is a key characteristic of asthma.Airway smooth muscle(ASM)cell hypertrophy and hyperplasia contributes to AWR.Glucocorticoids,whi...OBJECTIVE Airway wall remodeling(AWR),which refers to structural changes in the airway,is a key characteristic of asthma.Airway smooth muscle(ASM)cell hypertrophy and hyperplasia contributes to AWR.Glucocorticoids,which are used as first line therapy for the treatment of asthma,reduce ASM proliferation but the magnitude of their anti-proliferative actions is dependent on the mitogen used.Moreover,glucocorticoid therapy is accompanied by many side effects.Artesunate,a semi-synthetic artemisinin derivative,has been widely used to treat malaria with minimal toxicity.Artesunate has been shown to attenuate allergic airway inflammation in mice.However,its role in treating AWR in asthma is not known.In this study,we hypothesize that artesunate has anti-proliferative actions on ASM cells,potentially reversing AWR.METHODS and RESULTS Quiescent primary human ASM cells were pre-treated(1h)with artesunate(3,10,30μmol·L-1)before being stimulated with either FBS(10%)or thrombin(0.3U·mL-1).Following 48 h stimulation with mitogen,cells were counted using a haemocytometer.Dexamethasone(Dex,100nmol·L-1)was used as a positive control.Artesunate concentration-dependently reduced cell number and the magnitude of inhibition appeared to be non-mitogen dependent.Moreover,we examined the effect of artesunate on two important signalling proteins involved in cell proliferation,ERK1/2phosphorylation and cyclin D1 protein levels.Artesunate reduced cyclin D1 protein levels significantly following 20 h stimulation with either thrombin or FBS but had no effect on ERK1/2 phosphorylation following 6h stimulation.Importantly,artesunate(30μmol·L-1),but not Dex,inhibited the phosphorylation of Akt,which is upstream of cyclin D1.Next,we show that the inhibitory effect of artesunate,but not Dex,on ASM cell number is retained at least 24h post-treatment following stimulation with FBS.In an acute murine model of allergic asthma,artesunate treatment decreased sm-α-actin positive cells and cyclin D1 protein abundance in the ovalbumin sensitized and展开更多
文摘目的: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。
文摘OBJECTIVE Airway wall remodeling(AWR),which refers to structural changes in the airway,is a key characteristic of asthma.Airway smooth muscle(ASM)cell hypertrophy and hyperplasia contributes to AWR.Glucocorticoids,which are used as first line therapy for the treatment of asthma,reduce ASM proliferation but the magnitude of their anti-proliferative actions is dependent on the mitogen used.Moreover,glucocorticoid therapy is accompanied by many side effects.Artesunate,a semi-synthetic artemisinin derivative,has been widely used to treat malaria with minimal toxicity.Artesunate has been shown to attenuate allergic airway inflammation in mice.However,its role in treating AWR in asthma is not known.In this study,we hypothesize that artesunate has anti-proliferative actions on ASM cells,potentially reversing AWR.METHODS and RESULTS Quiescent primary human ASM cells were pre-treated(1h)with artesunate(3,10,30μmol·L-1)before being stimulated with either FBS(10%)or thrombin(0.3U·mL-1).Following 48 h stimulation with mitogen,cells were counted using a haemocytometer.Dexamethasone(Dex,100nmol·L-1)was used as a positive control.Artesunate concentration-dependently reduced cell number and the magnitude of inhibition appeared to be non-mitogen dependent.Moreover,we examined the effect of artesunate on two important signalling proteins involved in cell proliferation,ERK1/2phosphorylation and cyclin D1 protein levels.Artesunate reduced cyclin D1 protein levels significantly following 20 h stimulation with either thrombin or FBS but had no effect on ERK1/2 phosphorylation following 6h stimulation.Importantly,artesunate(30μmol·L-1),but not Dex,inhibited the phosphorylation of Akt,which is upstream of cyclin D1.Next,we show that the inhibitory effect of artesunate,but not Dex,on ASM cell number is retained at least 24h post-treatment following stimulation with FBS.In an acute murine model of allergic asthma,artesunate treatment decreased sm-α-actin positive cells and cyclin D1 protein abundance in the ovalbumin sensitized and
