The Multi-Faceted Extracellular Matrix: Unlocking Its Secrets for Understanding the Perpetuation of Lung Fibrosis

Abstract

Lung fibrosis is currently thought to stem from an aberrant wound healing response after recurring (micro) injuries in the lung epithelium, together with disrupted crosstalk between epithelial and stromal cells. An important factor in lung fibrosis is the abnormal deposition of extracellular matrix (ECM). In this review, we extend the view of ECM to summarize how aberrant structural organization and degradation of ECM contributes to (perpetuation of) lung fibrosis. Fibrotic changes in ECM including altered composition, such as increased collagens, coupled with mechanical properties, such as increased stiffness or abnormal fiber crosslinking, promote profibrotic responses in cells in this microenvironment. Similarly, changes in matrix degrading enzymes and release of degradation products from ECM proteins also perpetuate cellular fibrotic responses. In lung fibrosis, irreversible ECM structure, organization, and architectural alterations drive a perpetuating fibrotic response. Targeting strategies abrogating the abnormal ECM or ECM-degrading enzymes accompanied by prognostic and/or diagnostic approaches based on ECM fragments may provide novel alternatives to current therapeutic approaches for lung fibrosis.