Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis.
Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis.
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DOI：
10.1136/thoraxjnl-2013-204596
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发表时间：
2015-01
期刊：
影响因子：
10
通讯作者：
Arron JR
中科院分区：
文献类型：
--
作者：
DePianto DJ;Chandriani S;Abbas AR;Jia G;N'Diaye EN;Caplazi P;Kauder SE;Biswas S;Karnik SK;Ha C;Modrusan Z;Matthay MA;Kukreja J;Collard HR;Egen JG;Wolters PJ;Arron JR
特发性肺纤维化(IPF)肺组织病理变化具有微观的时空异质性，可能与疾病的病理生理介质和临床进展的异质性有关。我们评估了基因表达模式、病理特征和系统生物标记物之间的关系，以确定反映IPF患者总体疾病负担的生物标记物。肺活检的基因表达微阵列(N=40个IPF；8个对照)和免疫组织化学分析(N=22个IPF；8个对照)。IPF患者中MMP3和CXCL13的临床特征和血液生物标记物水平(N=80)。2940个基因在IPF和对照组中的表达差异有统计学意义(|倍数变化|>；1.5，p<；0.05)。两组与细支气管上皮或淋巴集合体相关的共调控基因在IPF人群中表现出显著的异质性。细支气管团和淋巴团的基因表达与相邻组织切片上免疫组织化学确定的毛细支气管化程度和淋巴集合体的程度相对应。细支气管束中编码的MMP3和淋巴系中编码的CXCL13的血清水平升高与疾病严重程度和生存时间缩短相对应(MMP3和CXCL13分别为10−7和10−5；COX比例风险模型)。IPF肺组织的微观病理异质性对应于与毛细支气管化和淋巴聚集相关的特定基因表达模式。MMP3和CXCL13是反映这些病理特征在整个肺组织中的总负担的系统性生物标记物。在IPF的介入研究中，这些生物标记物可能作为疾病活动性的预测和/或替代生物标记物具有临床价值。
There is microscopic spatial and temporal heterogeneity of pathologic changes in idiopathic pulmonary fibrosis (IPF) lung tissue, which may relate to heterogeneity in pathophysiological mediators of disease and clinical progression. We assessed relationships between gene expression patterns, pathological features, and systemic biomarkers to identify biomarkers that reflect the aggregate disease burden in IPF patients. Gene expression microarrays (N=40 IPF; 8 controls) and immunohistochemical analyses (N=22 IPF; 8 controls) of lung biopsies. Clinical characterization and blood biomarker levels of MMP3 and CXCL13 in a separate cohort of IPF patients (N=80). 2940 genes were significantly differentially expressed between IPF and control samples (|fold change| > 1.5, p < 0.05). Two clusters of co-regulated genes related to bronchiolar epithelium or lymphoid aggregates exhibited substantial heterogeneity within the IPF population. Gene expression in bronchiolar and lymphoid clusters corresponded to the extent of bronchiolization and lymphoid aggregates determined by immunohistochemistry in adjacent tissue sections. Elevated serum levels of MMP3, encoded in the bronchiolar cluster, and CXCL13, encoded in the lymphoid cluster, corresponded to disease severity and shortened survival time (p < 10−7 for MMP3 and p < 10−5 for CXCL13; Cox proportional hazards model). Microscopic pathological heterogeneity in IPF lung tissue corresponds to specific gene expression patterns related to bronchiolization and lymphoid aggregates. MMP3 and CXCL13 are systemic biomarkers that reflect the aggregate burden of these pathological features across total lung tissue. These biomarkers may have clinical utility as prognostic and/or surrogate biomarkers of disease activity in interventional studies in IPF.
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影响因子：
3.7
作者：
Seibold MA;Smith RW;Urbanek C;Groshong SD;Cosgrove GP;Brown KK;Schwarz MI;Schwartz DA;Reynolds SD
通讯作者：
Reynolds SD
影响因子：
5
作者：
Chilosi, M;Poletti, V;Doglioni, C
通讯作者：
Doglioni, C
影响因子：
4.6
作者：
Leslie, Kevin O.
通讯作者：
Leslie, Kevin O.
影响因子：
9.6
作者：
Lettieri, CJ;Nathan, SD;Shorr, AF
通讯作者：
Shorr, AF
DOI：
10.1164/rccm.201203-0506oc
发表时间：
2013-04-01
影响因子：
24.7
作者：
Kahloon, Rehan A.;Xue, Jianmin;Duncan, Steven R.
通讯作者：
Duncan, Steven R.