Baseline Stiffness Modulates the Non-Linear Response to Stretch of the Extracellular Matrix in Pulmonary Fibrosis.

Constança Júnior,Maria Narciso,Daniel Navajas,Ramon Farré,Esther Marhuenda,Jorge Otero,Isaac Almendros,Núria Gavara

doi:10.3390/ijms222312928

Abstract

Pulmonary fibrosis (PF) is a progressive disease that disrupts the mechanical homeostasis of the lung extracellular matrix (ECM). These effects are particularly relevant in the lung context, given the dynamic nature of cyclic stretch that the ECM is continuously subjected to during breathing. This work uses an in vivo model of pulmonary fibrosis to characterize the macro- and micromechanical properties of lung ECM subjected to stretch. To that aim, we have compared the micromechanical properties of fibrotic ECM in baseline and under stretch conditions, using a novel combination of Atomic Force Microscopy (AFM) and a stretchable membrane-based chip. At the macroscale, fibrotic ECM displayed strain-hardening, with a stiffness one order of magnitude higher than its healthy counterpart. Conversely, at the microscale, we found a switch in the stretch-induced mechanical behaviour of the lung ECM from strain-hardening at physiological ECM stiffnesses to strain-softening at fibrotic ECM stiffnesses. Similarly, we observed solidification of healthy ECM versus fluidization of fibrotic ECM in response to stretch. Our results suggest that the mechanical behaviour of fibrotic ECM under stretch involves a potential built-in mechanotransduction mechanism that may slow down the progression of PF by steering resident fibroblasts away from a pro-fibrotic profile.

Highlights

Pulmonary fibrosis (PF) is a devastating disease that causes progressive and irreversible destruction of the lung tissue architecture through scaring
This proposed cross-talk between matrix stiffening and fibroblast dysregulation has to be considered in light of the fact that the mechanical properties of the extracellular matrix (ECM) may be dynamically modulated by cyclic stretch, which is an intrinsic characteristic of lung tissue
The information gathered through macroscale tensile tests is not best suited to fully characterize the actual lung micromechanical environment and the mechanosensing events it may trigger at the cellular level

Summary

Introduction

Pulmonary fibrosis (PF) is a devastating disease that causes progressive and irreversible destruction of the lung tissue architecture through scaring. Two anti-fibrotic drugs, pirfenidone and nintedanib, have been approved to slow down the progression of PF These drugs are believed to act by inhibiting fibroblast proliferation and differentiation into myofibroblasts, likely reducing their ability to modify the composition and architecture of the lung extracellular matrix (ECM) [2]. In this regard, it remains unclear how alterations of the ECM are linked to changes in the mechanical behaviour of the lung in PF and how cells respond to these alterations.

Methods

Results

Conclusion