Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis.

Autor: DePianto DJ; Genentech Research and Early Development, South San Francisco, California, USA., Chandriani S; Genentech Research and Early Development, South San Francisco, California, USA Novartis Institutes for Biomedical Research, Emeryville, California, USA., Abbas AR; Genentech Research and Early Development, South San Francisco, California, USA., Jia G; Genentech Research and Early Development, South San Francisco, California, USA., N'Diaye EN; Genentech Research and Early Development, South San Francisco, California, USA., Caplazi P; Genentech Research and Early Development, South San Francisco, California, USA., Kauder SE; Genentech Research and Early Development, South San Francisco, California, USA., Biswas S; Genentech Research and Early Development, South San Francisco, California, USA., Karnik SK; Genentech Research and Early Development, South San Francisco, California, USA Gilead Sciences, Foster City, California, USA., Ha C; Genentech Research and Early Development, South San Francisco, California, USA., Modrusan Z; Genentech Research and Early Development, South San Francisco, California, USA., Matthay MA; Department of Medicine, University of California, San Francisco, California, USA., Kukreja J; Department of Surgery, University of California, San Francisco, California, USA., Collard HR; Department of Medicine, University of California, San Francisco, California, USA., Egen JG; Genentech Research and Early Development, South San Francisco, California, USA., Wolters PJ; Department of Medicine, University of California, San Francisco, California, USA., Arron JR; Genentech Research and Early Development, South San Francisco, California, USA.
Jazyk: angličtina
Zdroj: Thorax [Thorax] 2015 Jan; Vol. 70 (1), pp. 48-56. Date of Electronic Publication: 2014 Sep 12.
DOI: 10.1136/thoraxjnl-2013-204596
Abstrakt: Background: There is microscopic spatial and temporal heterogeneity of pathological 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 patients with IPF.
Methods: Gene expression microarrays (N=40 IPF; 8 controls) and immunohistochemical analyses (N=22 IPF; 8 controls) of lung biopsies. Clinical characterisation and blood biomarker levels of MMP3 and CXCL13 in a separate cohort of patients with IPF (N=80).
Results: 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 bronchiolisation 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).
Conclusions: Microscopic pathological heterogeneity in IPF lung tissue corresponds to specific gene expression patterns related to bronchiolisation 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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Databáze: MEDLINE
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