Idiopathic pulmonary fibrosis: Disease mechanisms and drug development

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown cause characterized by relentless scarring of the lung parenchyma leading to reduced quality of life and earlier mortality. IPF is an age-related disorder, and with the population aging worldwide, the economic burden of IPF is expected to steadily increase in the future. The mechanisms of fibrosis in IPF remain elusive, with favored concepts of disease pathogenesis involving recurrent microinjuries to a genetically predisposed alveolar epithelium, followed by an aberrant reparative response characterized by excessive collagen deposition. Pirfenidone and nintedanib are approved for treatment of IPF based on their ability to slow functional decline and disease progression; however, they do not offer a cure and are associated with tolerability issues. In this review, we critically discuss how cutting-edge research in disease pathogenesis may translate into identification of new therapeutic targets, thus facilitate drug discovery. There is a growing portfolio of treatment options for IPF. However, targeting the multitude of profibrotic cytokines and growth factors involved in disease pathogenesis may require a combination of therapeutic strategies with different mechanisms of action.

Keywords: Disease mechanisms; Genomics; Idiopathic pulmonary fibrosis; Pathogenesis; Single-cell biology; Stem cells; Therapeutic targets; Treatment.

Figure 1.

Fibroblastic foci are discrete proliferations of myofibroblasts in myxoid stroma indicative of active fibrosis (blue arrow) often covered by activated alveolar epithelial cells representing the site of acute lung injury (squares) and with peripheral angiogenetic phenomena with multiple small capillaries (triangles) (A, hematoxylin-eosin stain). Fibroblastic foci may be investigated for protein expression by immunohistochemistry (B, up-regulation of c-MET in alveolar epithelial cells; squares; C, upregulation of the epithelial-to-mesenchymal transition protein Twist in myofibroblasts; arrow). Fluorescent in situ hybridization analysis of c-MET (D) and molecular investigation of c-MET mutations (electropherogram, E). Microdissection of fibroblastic foci from transbronchial biopsy allows obtaining an adequate amount of DNA/RNA for selective multiplex genomic and proteomic analysis (F).

Figure 2.

Selected potential targets in IPF