The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma
The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma
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DOI：
10.1164/rccm.201304-0775oc
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发表时间：
2013-11-15
影响因子：
24.7
通讯作者：
Leung, Donald Y. M.
中科院分区：
文献类型：
--
作者：
Goleva, Elena;Jackson, Leisa P.;Leung, Donald Y. M.
基本原理：气道微生物组在哮喘皮质类固醇反应中的作用尚不清楚。目的：检测皮质类固醇抵抗（CR）哮喘患者的气道微生物组组成，并将其与皮质类固醇敏感（CS）哮喘患者和正常对照受试者进行比较，探讨哮喘受试者气道中的细菌是否可能指导细胞对皮质类固醇反应的改变。方法：对39例哮喘患者和12例健康对照者的支气管肺泡灌洗（BAL）样本进行16 S rRNA基因测序。在哮喘受试者中，皮质类固醇的反应性的特点，BAL巨噬细胞刺激与病原体与微生物，并通过实时聚合酶链反应分析皮质类固醇调节基因的表达和细胞p38丝裂原活化蛋白激酶（MAPK）activation. Measures和主要结果：39例哮喘患者中，29例CR和10例CS。来自CR和CS哮喘受试者的BAL微生物组在门水平上的丰富度、均匀度、多样性和群落组成方面没有差异，但在属水平上确实存在差异，14名CR哮喘受试者的属扩展明显。哮喘气道巨噬细胞与副流感嗜血杆菌（一种仅在CR哮喘气道中发现的唯一扩增的潜在病原体）预孵育导致p38 MAPK激活，IL-8（P < 0.01）和丝裂原活化激酶磷酸酶1（P <0.01）mRNA表达增加，皮质类固醇反应受到抑制（P < 0.05）。在暴露于产黑色素普雷沃氏菌后未观察到这一点。抑制转化生长因子-β-相关激酶-1（TAK 1）（MAPK的上游激活剂）而非p38 MAPK可恢复细胞对皮质类固醇的敏感性。[图形]结论：CR哮喘受试者的一个子集表现出特定革兰氏阴性菌的气道扩张，其触发TAK 1/MAPK激活并诱导皮质类固醇抵抗。TAK 1抑制恢复了细胞对皮质类固醇的敏感性。
Rationale: The role of airway microbiome in corticosteroid response in asthma is unknown.Objectives: To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids.Methods: 16S rRNA gene sequencing was performed on bronchoalveolar lavage(BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation.Measurements and Main Results: Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-beta-associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids.[GRAPHICS]Conclusions: A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.