Heterogeneous Gene Signatures in Idiopathic Pulmonary Fibrosis
Heterogeneous Gene Signatures in Idiopathic Pulmonary Fibrosis
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 for MMP3 and p<10 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.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal fibrotic lung disease with no known cause and a median survival of ~3 years. The clinical course within the population of patients with IPF is variable, ranging from a slow, steady loss of lung function over 5 or more years to rapid progression and death within 1–2 years of diagnosis to relatively stable disease punctuated by intermittent precipitous declines in lung function resulting from acute exacerbations. The mechanisms underlying this variability in disease progression within the population of patients with IPF are poorly understood.
The fibrosis observed in IPF is hypothesised to originate from an irregular wound healing response triggered by a loss of integrity in the alveolar epithelium followed by persistent profibrotic signals that fail to resolve. The microscopic presentation of IPF in diseased lung tissue is spatially and temporally heterogeneous. Regions of fibroblast accumulation and active matrix remodelling can exist between areas of normal-appearing lung and mature scar tissue. A complex mixture of resident and infiltrating cell types can be found in these distinct regions of remodelled lung. It is therefore important to develop a deeper understanding of IPF biology at a local level to better characterise the location and consequences of aberrant signalling processes.
A challenge in designing interventional clinical studies in IPF is the lack of a robust means of identifying and controlling for biological heterogeneity, and of selecting patients at risk for outcomes of interest. Non-invasive biomarkers that reflect the activity of specific pathways and aggregate fibrotic burden across a given patient's total lung tissue could be valuable tools in identifying stage of disease, and could aid in selecting treatments and monitoring biological responses to therapy. In this study we used gene expression profiling and histology to characterise pathological patterns that display heterogeneous expression levels within lung tissue from a population of patients with IPF, and identified systemic biomarkers related to these patterns that correspond to disease severity. The coordinated analyses of gene expression, histology and peripheral biomarkers provide the opportunity to integrate insight into IPF pathogenesis at multiple levels, with the potential to contribute to the development of novel therapies and diagnostics.
Abstract and Introduction
Abstract
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 for MMP3 and p<10 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.
Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal fibrotic lung disease with no known cause and a median survival of ~3 years. The clinical course within the population of patients with IPF is variable, ranging from a slow, steady loss of lung function over 5 or more years to rapid progression and death within 1–2 years of diagnosis to relatively stable disease punctuated by intermittent precipitous declines in lung function resulting from acute exacerbations. The mechanisms underlying this variability in disease progression within the population of patients with IPF are poorly understood.
The fibrosis observed in IPF is hypothesised to originate from an irregular wound healing response triggered by a loss of integrity in the alveolar epithelium followed by persistent profibrotic signals that fail to resolve. The microscopic presentation of IPF in diseased lung tissue is spatially and temporally heterogeneous. Regions of fibroblast accumulation and active matrix remodelling can exist between areas of normal-appearing lung and mature scar tissue. A complex mixture of resident and infiltrating cell types can be found in these distinct regions of remodelled lung. It is therefore important to develop a deeper understanding of IPF biology at a local level to better characterise the location and consequences of aberrant signalling processes.
A challenge in designing interventional clinical studies in IPF is the lack of a robust means of identifying and controlling for biological heterogeneity, and of selecting patients at risk for outcomes of interest. Non-invasive biomarkers that reflect the activity of specific pathways and aggregate fibrotic burden across a given patient's total lung tissue could be valuable tools in identifying stage of disease, and could aid in selecting treatments and monitoring biological responses to therapy. In this study we used gene expression profiling and histology to characterise pathological patterns that display heterogeneous expression levels within lung tissue from a population of patients with IPF, and identified systemic biomarkers related to these patterns that correspond to disease severity. The coordinated analyses of gene expression, histology and peripheral biomarkers provide the opportunity to integrate insight into IPF pathogenesis at multiple levels, with the potential to contribute to the development of novel therapies and diagnostics.