Distal Lung Microenvironment Triggers Release of Mediators Recognized as Potential Systemic Biomarkers for Idiopathic Pulmonary Fibrosis.

Dimitrios Kalafatis,Åsa M Wheelock,Göran Dellgren,Anna Löfdahl,Linda Elowsson Rendin,Magnus Sköld,Gunilla Westergren-Thorsson,Per Näsman

doi:10.3390/ijms222413421

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an unmet need of biomarkers that can aid in the diagnostic and prognostic assessment of the disease and response to treatment. In this two-part explorative proteomic study, we demonstrate how proteins associated with tissue remodeling, inflammation and chemotaxis such as MMP7, CXCL13 and CCL19 are released in response to aberrant extracellular matrix (ECM) in IPF lung. We used a novel ex vivo model where decellularized lung tissue from IPF patients and healthy donors were repopulated with healthy fibroblasts to monitor locally released mediators. Results were validated in longitudinally collected serum samples from 38 IPF patients and from 77 healthy controls. We demonstrate how proteins elevated in the ex vivo model (e.g., MMP7), and other serum proteins found elevated in IPF patients such as HGF, VEGFA, MCP-3, IL-6 and TNFRSF12A, are associated with disease severity and progression and their response to antifibrotic treatment. Our study supports the model’s applicability in studying mechanisms involved in IPF and provides additional evidence for both established and potentially new biomarkers in IPF.

Highlights

Idiopathic pulmonary fibrosis (IPF) is an irreversible interstitial pneumonia of progressive nature
We have shown that fibroblasts in IPF lung become activated in synthesizing increased amounts of collagens to uphold a fibrotic tissue with typical IPF features, of which collagen I has been described to act as a scaffold for angiogenesis [56]
This study was designed in two parts; firstly, to examine local fibroblast activities in IPF using a novel ex vivo model, and secondly to compare and establish the systemic proteomic profile in serum collected at baseline and follow up from IPF patients

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is an irreversible interstitial pneumonia of progressive nature. The variability in disease course is evident in IPF where some patients demonstrate a slow decline in lung function, while others present an accelerated disease progression or even fatal respiratory insufficiency [2]. The heterogeneity of IPF creates difficulties in predicting disease course, warranting the need for effective diagnostic and prognostic biomarkers. There are no treatments available that can reverse or halt the progression of fibrosis despite promising results of early drug candidates in preclinical studies. Both in vitro and in vivo models have not fully recapitulated the complex fibrogenic activity that occurs in the lungs of IPF patients. There is a need for preclinical models mimicking events in the fibrotic processes that may help in identifying key disease mechanisms and possible therapeutic targets

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Results

Discussion

Conclusion