Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages.
Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages.
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DOI：
10.1016/j.jaci.2008.07.007
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发表时间：
2008-09
期刊：
影响因子：
--
通讯作者：
Leung DY
中科院分区：
文献类型：
--
作者：
Goleva E;Hauk PJ;Hall CF;Liu AH;Riches DW;Martin RJ;Leung DY
皮质类固醇抵抗型哮喘的原因尚不清楚。应用BAL细胞进行基因芯片分析，研究激素抵抗(CR)和敏感型(CS)哮喘患者的BAL细胞差异表达与激素耐药的关系。根据FEV1%预测在口服泼尼松一周疗程后改善，患者的特征为CR或CS。用实时荧光定量聚合酶链式反应和酶联免疫吸附试验验证了所选基因靶点的表达。基因芯片分析显示，CR哮喘患者BAL细胞中肿瘤坏死因子α、IL-1α、IL-1β、IL-6、CXCL1、CXCL2、CXCL3、CXCL8、CCL3、CCL4、CCL20的转录水平显著升高(P<0.05)。这些发现在额外的BAL样本中得到了RT-PCR的证实，与细菌产物激活巨噬细胞的经典结果一致。相比之下，交替激活的巨噬细胞的标志物精氨酸酶I和CCL24减少。与内毒素信号通路激活相关的基因(Egr1、DUSP2、MAIL、TNFAIP3)在CR BAL样本中显著升高(p<；0.05)。经LAL法检测和气相色谱-质谱分析证实，这些患者BAL液中内毒素含量(1444.0±457.3 pg/mg总蛋白)显著高于CS哮喘患者(270.5±216.0 pg/mg总蛋白)。暴露于脂多糖可诱导正常单核细胞对地塞米松(DEX)的功能性类固醇抵抗，表现为在DEX存在的情况下IL-6水平持续升高。在缓解性哮喘患者BAL液中检测到经典的巨噬细胞激活和诱导内毒素信号通路，以及高水平的内毒素，提示内毒素暴露可能参与缓解性哮喘的发病。
The cause of corticosteroid resistant asthma is unknown. To perform gene microarray analyses using BAL cells from well-characterized corticosteroid resistant (CR) and sensitive (CS) asthmatics to elucidate the differential expression of genes that contribute to the development of corticosteroid resistance. The patients were characterized as CR or CS based on FEV1% predicted improvement after one week course of oral prednisone. Expression of selected gene targets was verified by real time PCR and by ELISA. Microarray analyses demonstrated significantly higher levels (over three-fold increase, p<0.05) of transcripts for TNFα, IL-1α, IL-1β, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, CCL20 in BAL cells of CR asthmatics. These findings, confirmed by RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively-activated macrophages, Arginase I and CCL24, were decreased. Genes associated with activation of the LPS signaling pathway (EGR1, DUSP2, MAIL, TNFAIP3) were significantly elevated in CR BAL samples (p<0.05). These patients had significantly higher amounts (1444.0±457.3 pg per mg of total protein) of LPS in BAL fluid than CS asthmatics (270.5±216.0 pg; p<0.05) as detected by LAL assay and confirmed by gas chromatography mass spectrometry analysis. Pronged exposure to LPS induced functional steroid resistance to dexamethasone (DEX) in normal monocytes, demonstrated by persistently elevated IL-6 levels in the presence of DEX. Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from CR asthmatics suggest that LPS exposure may contribute to CR asthma.
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影响因子：
6.7
作者：
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通讯作者：
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DOI：
10.1164/rccm.200507-1046oc
发表时间：
2006-03-15
影响因子：
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作者：
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通讯作者：
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影响因子：
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