Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal fibrotic lung disease that occurs primarily in middle-aged and elderly adults. It is a major cause of morbidity and mortality. With an increase in life expectancy, the economic burden of IPF is expected to continuously rise in the near future. Although the exact pathophysiological mechanisms underlying IPF remain not known. Significant progress has been made in our understanding of the pathogenesis of this devastating disease in last decade. The current paradigm assumes that IPF results from sustained or repetitive lung epithelial injury and subsequent activation of fibroblasts and myofibroblast differentiation. Persistent myofibroblast phenotype contributes to excessive deposition of the extracellular matrix (ECM) and aberrant lung repair, leading to tissue scar formation, distortion of the alveolar structure, and irreversible loss of lung function. Treatments of patients with IPF by pirfenidone and nintedanib have shown significant reduction of lung function decline and slowing of disease progression in patients with IPF. However, these drugs do not cure the disease. In this review, we discuss recent advances on the pathogenesis of IPF and highlight the development of novel therapeutic strategies against the disease.

Keywords: alveolar epithelial cells; extracellular matrix; fibroblasts; idiopathic pulmonary fibrosis; pathogenesis.

FIGURE 1

Pathogenesis of idiopathic pulmonary fibrosis. Genetic factors affect the integrity of epithelial cells, environmental factors and aging-related changes will trigger epigenetic reprogramming. The combined action of the three factors will cause epithelial cell damage and trigger the abnormal activation of epithelial cells. Activated epithelial cells secretes a large number of cytokines such as TGF-β which consequently promotes fibroblast migration and proliferation, and also promote fibroblasts to differentiate into myofibroblasts. Myofibroblasts secrete large amounts of ECM, leading to ECM deposition. In addition, epithelial cell damage, disfunction and exhaustion of stem cells, abnormal deposition of extracellular matrix and matrix stiffness play a vital role in progression of abnormal lung fibrosis and remodeling of lung structure.