Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1.
Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1.
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DOI：
10.1016/j.jaci.2015.11.020
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Howarth PH
中科院分区：
文献类型：
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作者：
Hinks TSC;Brown T;Lau LCK;Rupani H;Barber C;Elliott S;Ward JA;Ono J;Ohta S;Izuhara K;Djukanović R;Kurukulaaratchy RJ;Chauhan A;Howarth PH
严重哮喘患者的疾病异质性及其与炎症机制的关系仍然知之甚少。我们的目的是根据分析哮喘患者的血液和痰参数来确定和复制临床病理内型。从两个不同的中心招募194名哮喘患者和21名对照受试者进行了详细的临床评估、痰诱导和静脉切开术。通过拓扑数据分析和贝叶斯网络分析，分析了103个临床、生理和炎症参数。严重哮喘与焦虑、抑郁、肥胖、鼻窦症状、生活质量下降和炎症变化相关，包括痰中几丁质酶3样蛋白1 （YKL-40）和基质金属蛋白酶（MMP） 1、3、8和12水平升高。拓扑数据分析确定了在两个地理队列中重复的6个临床病理集群：年轻，轻度粒细胞缺乏症；年龄较大，鼻窦疾病；肥胖，MMP水平高；抗类固醇TH2介导的嗜酸性粒细胞；混合性粒细胞伴严重梗阻；嗜中性粒细胞，低骨膜蛋白水平，严重梗阻。痰中IL-5水平在严重的特别是嗜酸性粒细胞型患者中升高，而IL-13水平被抑制，IL-17水平在集群之间没有差异。贝叶斯网络分析将临床特征从错综复杂的炎症途径中分离出来。YKL-40水平与中性粒细胞哮喘、髓过氧化物酶、IL-8、IL-6和IL-6可溶性受体水平密切相关。MMP1、MMP3、MMP8和MMP12水平与严重哮喘相关，与痰IL-5水平呈正相关，与IL-13水平负相关。在2个不同的队列中，我们根据血液和诱导痰的测量确定并复制了6个临床病理集群。我们的数据强调了临床特征和潜在炎症之间的脱节，表明IL-5的产生相对来说是类固醇不敏感的，并强调了中性粒细胞炎症患者中YKL-40的表达和严重哮喘患者中MMPs的表达。
Disease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood. We aimed to identify and replicate clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients. One hundred ninety-four asthmatic patients and 21 control subjects recruited from 2 separate centers underwent detailed clinical assessment, sputum induction, and phlebotomy. One hundred three clinical, physiologic, and inflammatory parameters were analyzed by using topological data analysis and Bayesian network analysis. Severe asthma was associated with anxiety and depression, obesity, sinonasal symptoms, decreased quality of life, and inflammatory changes, including increased sputum chitinase 3–like protein 1 (YKL-40) and matrix metalloproteinase (MMP) 1, 3, 8, and 12 levels. Topological data analysis identified 6 clinicopathobiologic clusters replicated in both geographic cohorts: young, mild paucigranulocytic; older, sinonasal disease; obese, high MMP levels; steroid resistant TH2 mediated, eosinophilic; mixed granulocytic with severe obstruction; and neutrophilic, low periostin levels, severe obstruction. Sputum IL-5 levels were increased in patients with severe particularly eosinophilic forms, whereas IL-13 was suppressed and IL-17 levels did not differ between clusters. Bayesian network analysis separated clinical features from intricately connected inflammatory pathways. YKL-40 levels strongly correlated with neutrophilic asthma and levels of myeloperoxidase, IL-8, IL-6, and IL-6 soluble receptor. MMP1, MMP3, MMP8, and MMP12 levels were associated with severe asthma and were correlated positively with sputum IL-5 levels but negatively with IL-13 levels. In 2 distinct cohorts we have identified and replicated 6 clinicopathobiologic clusters based on blood and induced sputum measures. Our data underline a disconnect between clinical features and underlying inflammation, suggest IL-5 production is relatively steroid insensitive, and highlight the expression of YKL-40 in patients with neutrophilic inflammation and the expression of MMPs in patients with severe asthma.