Research Progress in the Molecular Mechanisms, Therapeutic Targets, and Drug Development of Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Recent studies have identified the key role of crosstalk between dysregulated epithelial cells, mesenchymal, immune, and endothelial cells in IPF. In addition, genetic mutations and environmental factors (e.g., smoking) have also been associated with the development of IPF. With the recent development of sequencing technology, epigenetics, as an intermediate link between gene expression and environmental impacts, has also been reported to be implicated in pulmonary fibrosis. Although the etiology of IPF is unknown, many novel therapeutic targets and agents have emerged from clinical trials for IPF treatment in the past years, and the successful launch of pirfenidone and nintedanib has demonstrated the promising future of anti-IPF therapy. Therefore, we aimed to gain an in-depth understanding of the underlying molecular mechanisms and pathogenic factors of IPF, which would be helpful for the diagnosis of IPF, the development of anti-fibrotic drugs, and improving the prognosis of patients with IPF. In this study, we summarized the pathogenic mechanism, therapeutic targets and clinical trials from the perspective of multiple cell types, gene mutations, epigenetic and environmental factors.

Keywords: cells crosstalk; emerging drugs; epigenetics; gene mutations; idiopathic pulmonary fibrosis.

FIGURE 1

The pathological process of idiopathic pulmonary fibrosis. (A) After normal alveoli are damaged and abnormally repaired, irreversible lung function deterioration occurs. Normal alveolus has a complete basement membrane and gas exchange function. (B) When the basement membrane continuity is disrupted by external injury, the damaged capillaries and activated AECs release inflammatory signals and coagulation factors, forming a local inflammatory microenvironment. (C) If the damage persists, abnormal repair will be initiated. Lung mesenchymal progenitors, fibrocytes recruited to the lung, and endothelial cells undergoing EMT can aggregate to form fibroblasts foci and differentiate into matrix-secreting myofibroblasts. To compensate for the local blood supply to the alveoli, new blood vessels are gradually formed. (D) As fibroblast foci increased, more ECM was deposited and cross-linked together, triggering a deterioration in lung compliance and gas exchange function.

FIGURE 2

A schematic view of the roles of AECs, immune cells and fibroblasts. (A) Alveolar epithelial cells/endothelial cells participate in IPF via ER stress/UPR, EMT, coagulation cascade, and the secretion of a variety of signaling factors. (B) The balance of Th1/Th2 and M1/M2. (C) The sources of fibroblasts and the fibroblast-to-myofibroblasts differentiation.

FIGURE 3

A schematic view of the role of ECM in IPF. (A) Matrkines, which contain multiple degradation products of the ECM, exert dual pro- and anti-fibrotic roles in IPF. (B) The ECM is involved in the phenotypic reprogramming of fibroblasts and AECs by modifying key signaling molecules. (C) After binding specific ECM ligands to the ectodomain of integrins, integrins bind to the cytoskeleton and various signaling proteins through their cytoplasmic tails, translating the mechanical force of cytoskeleton contraction and ECM stiffness into biochemical signals. (D) Integrins activate TGF-β-dependent fibrosis by releasing TGF-β through stretch force generated by actin-cytoskeleton interactions.

FIGURE 4

The process of surfactant secretion and the potential pathological mechanism of MUC5B mutation. (A) The surfactant precursors are synthesized on the endoplasmic reticulum, followed by Golgi modifications, and finally secreted into the periphery by cytosolic exocytosis of the lamellar body. (B) MUC5B mutation may promote the retention of harmful substances in the lung and interfere with the normal repair of AEC.

FIGURE 5

The roles of DNA methylation and histone modification in IPF. (A) DNA methylation affects the expression of gene associated with fibrosis and produces a pro-fibrotic effect. (B) EZH2 and HADC induce changes in gene expression associated with fibrosis by affecting histone modifications.