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

Abstract

Background 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. Methods 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). 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 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). Conclusions 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.

αvβ6 integrin may be a potential prognostic biomarker in interstitial lung disease

“…Studies of biopsies from patients with IPF have assessed whether the fibroblastic foci correlate with reduced survival but the results have not been conclusive [7,8], and molecular phenotyping for transforming growth factor (TGF)-β signalling molecules did not show any relationship to survival [9]. Serum and plasma biomarkers, such as KL-6 [10], CXCL13 [11] CCL18 [12], matrix metalloproteinase (MMP)-3 [13] and MMP-7 [14], have been shown to have prognostic value in IPF, although how they reflect underlying disease pathogenesis or whether they change in response to therapy remains uncertain. Recently, it was hypothesised that there may be two distinct endotypes of disease, related to disrupted bronchiolisation and lymphoid aggregates, which may prove useful in developing interventional clinical trials [13].…”

Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study

“…Extracellular collagen fragments generated by these MMPs are then further digested by MMP-2 and -9 6 . In IPF markedly increased rates of ECM protein synthesis are, at least partially, offset by elevated MMP levels and activity 7 and MMP-1, -3 and -7 have even been identified as putative prognostic serum biomarkers 8,9 .…”

Molecular classification of idiopathic pulmonary fibrosis: Personalized medicine, genetics and biomarkers

“…135 Two clusters of co-regulated genes were found to be upregulated in IPF. The first cluster comprised genes related to the bronchiolar epithelium, and the second consisted of T-and B-cell markers, Fc receptor genes, and chemokines.…”