Anti-fibrotic strategies and pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) results from the dysregulated process of injury and repair, which promotes scarring of the lung tissue and deposition of collagen-rich extracellular matrix (ECM) components, that make the lung unphysiologically stiff. IPF presents a serious concern as its pathogenesis remains elusive, and current anti-fibrotic treatments are only effective in slowing rather than halting disease progression. The IPF disease pathogenesis is incompletely defined, complex and incorporates interplay between different fibrogenesis signaling pathways. Preclinical IPF experimental models used to validate drug candidates present significant limitations in modeling IPF pathobiology, with their limited time frame, simplicity and inaccurate representation of the disease and the mechanical influences of IPF. Potentially more accurate mimetic disease models that capture the cell-cell and cell-matrix interaction, such as 3D cultures, organoids and precision-cut lung slices (PCLS), may yield more meaningful clinical predictions for drug candidates. Recent advances in developing anti-fibrotic compounds have positioned drug towards targeting components of the fibrogenesis signaling pathway of IPF or the extracellular microenvironment. The major goals in this area of research focus on finding ways to reverse or halt the disease progression by utilizing more disease-relevant experimental models to improve the qualification of potential drug targets for treating pulmonary fibrosis.

Keywords: Anti-fibrotic compounds; Extracellular matrix; Fibrogenesis signaling pathways; Fibrosis experimental models; Idiopathic pulmonary fibrosis; Lung fibrosis; Nintedanib; Pirfenidone.