Released mediators in ex vivo 3D-model of lung fibrosis correspond to elevated serum biomarkers in IPF

Abstract

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with limited treatment options and a considerable diagnostic delay. Studies for diagnostic and prognostic biomarkers are therefore warranted. In an unpublished study, we discovered elevated levels of inflammatory and oncology-related proteins in a novel ex-vivo model where human healthy lung fibroblasts are cultured on decellularized lung tissue derived from IPF patients or healthy individuals. Aim: Evaluate potential biomarkers found elevated in ex vivo model in serum from a cohort of IPF patients. Methods: A panel of 92 proteins were examined with proximity extension assay in serum from 38 IPF patients and in 77 individuals with normal lung function. Protein data were correlated to clinical measures of disease severity. Results: After adjustment for multiple testing with Bonferroni correction, we were able to demonstrate that proteins elevated in the ex-vivo model, were also significantly elevated in serum from IPF patients compared to controls, with higher levels of CCL19, CXCL13 and MMP7 observed. In addition, MMP7 correlated negatively with both percent predicted forced vital capacity (FVC%, r= -0.48, p=0.0020) and total lung capacity (TLC%, r= -0.49, p=0.0017). Conclusion: We conclude that the ex vivo model may mimic fibrotic lung disease with elevated levels of CCL19, CXCL13 and MMP7 observed both ex-vivo and in IPF patients. An association with measures of disease severity strengthens our findings. Our results highlight the identified proteins in their roles as important drivers of fibrotic processes and the model’s applicability as an innovative way of studying pathological responses in IPF.