Abstract
BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need. Development of transformational therapies for IPF is challenging in part to due to lack of robust predictive biomarkers of prognosis and treatment response. Importantly, circulating biomarkers of IPF are limited and none are in clinical use.MethodsWe previously reported dysregulated pathways and new disease biomarkers in advanced IPF through RNA sequencing of lung tissues from a cohort of transplant-stage IPF patients (n = 36) in comparison to normal healthy donors (n = 19) and patients with acute lung injury (n = 11). Here we performed proteomic profiling of matching plasma samples from these cohorts through the Somascan-1300 SomaLogics platform.ResultsComparative analyses of lung transcriptomic and plasma proteomic signatures identified a set of 34 differentially expressed analytes (fold change (FC) ≥ ± 1.5, false discovery ratio (FDR) ≤ 0.1) in IPF samples compared to healthy controls. IPF samples showed strong enrichment of chemotaxis, tumor infiltration and mast cell migration pathways and downregulated extracellular matrix (ECM) degradation. Mucosal (CCL25 and CCL28) and Th2 (CCL17 and CCL22) chemokines were markedly upregulated in IPF and highly correlated within the subjects. The mast cell maturation chemokine, CXCL12, was also upregulated in IPF plasma (fold change 1.92, FDR 0.006) and significantly correlated (Pearson r = − 0.38, p = 0.022) to lung function (%predicted FVC), with a concomitant increase in the mast cell Tryptase, TPSB2. Markers of collagen III and VI degradation (C3M and C6M) were significantly downregulated (C3M p < 0.001 and C6M p < 0.0001 IPF vs control) and correlated, Pearson r = 0.77) in advanced IPF consistent with altered ECM homeostasis.ConclusionsOur study identifies a panel of tissue and circulating biomarkers with clinical utility in IPF that can be validated in future studies across larger cohorts.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need
Using well annotated lung tissue samples from a cohort of transplant stage IPF patients in comparison to acute lung injury and healthy controls, we previously reported a transcriptomic fingerprint of advanced IPF enriched in pathways of T-cell activation, immune response and extracellular matrix (ECM) remodeling [17]
Expression data were visualized using t-scholastic neighborhood enrichment (t-SNE), that showed a robust separation of the IPF samples from the control and Acute lung injury (ALI) samples (Fig. 1a)
Summary
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need. Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic and fatal lung disease with a huge unmet medical need [1,2,3]. Using well annotated lung tissue samples from a cohort of transplant stage IPF patients in comparison to acute lung injury and healthy controls, we previously reported a transcriptomic fingerprint of advanced IPF enriched in pathways of T-cell activation, immune response and ECM remodeling [17]. These studies identified novel gene associations to lung function as well as unique isoform regulation in IPF lung
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