Fibronectin's tensional state as a mechanical signature of fibrotic extracellular matrix in idiopathic pulmonary fibrosis models

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with limited treatment options. Emerging evidence suggests that the composition and mechanics of the extracellular matrix (ECM) play a crucial role in IPF pathogenesis; however, biomarkers that indicate altered ECM signatures are scarce. To demonstrate a direct relationship between ECM fiber tension and fibrosis progression, we established an in vitro fibrosis assay using patient-derived fibroblasts and the tension-sensitive fibronectin-binding peptide FnBPA5, whose multivalent binding to fibronectin is impaired by fiber strain. The system was validated using known fibrosis biomarkers at the protein and mRNA levels. Loss of fibronectin fiber tension not only acts as a marker for fibrosis, but as shown here, tension can be restored upon treatment with antifibrotic drugs, concomitant with improved biomarker data. The loss of fibronectin fiber tension was further corroborated ex vivo by probing fibrotic lung cryosections from bleomycin-treated mice with FnBPA5. Taken together, our results highlight the mechanical state of fibronectin fibers as a promising biomarker for IPF.