Pulmonary fibrosis: from mechanisms to therapies

Abstract

Pulmonary fibrosis (PF) is a chronic, progressive interstitial lung disease characterized by excessive deposition of extracellular matrix (ECM) and abnormal fibroblast proliferation, which is mainly caused by air pollution, smoking, aging, occupational exposure, environmental pollutants exposure, and microbial infections. Although antifibrotic agents such as pirfenidone and nintedanib, approved by the United States (US) Food and Drug Administration (FDA), can slow the decline in lung function and disease progression, their side effects and delivery inefficiency limit the overall prognosis of PF. Therefore, there is an urgent need to develop effective therapeutic targets and delivery approaches for PF in clinical settings. This review provides an overview of the pathogenic mechanisms, therapeutic drug targeting signaling pathways, and promising drug delivery strategies for treating PF.

Keywords: Drug delivery system; Pathogenic mechanisms; Pulmonary fibrosis; Therapeutic targets.

Fig. 1

Schematic representation of PF potential risk factors. Diverse risk factors, including intrinsic factors (including genetic factors and aging), and extrinsic factors (including air pollution, smoking, occupational exposure, environmental pollutants exposure, and microbial infections) contribute to PF. Image Created in https://BioRender.com

Fig. 2

Summary of the key effector cells in the initiation of PF. Following profibrotic factors stimulus, macrophages respond and produce inflammatory cytokines. Cytokines attract more immune cells, such as monocytes and neutrophils, which in turn produce more cytokines, creating a cycle of inflammation that damages the lung cells. In addition, activated fibroblasts (including those that originated from EMT and EndoMT ) stimulate the production of myofibroblasts as well as excessive ECM deposition which undergoes pathologic remodeling. Image Created in https://BioRender.com

Fig. 3

Overview of molecular signaling pathways in PF. In the TGF-β signaling, TGF-β binding to TGF-βRs activates the TGF-β-Smad signalings. In the Wnt signaling, activated DVL inhibits the destruction complex and then allows β-catenin accumulation to enter the nucleus where it can act together with either p300 or CBP as a transcriptional co-activator for TCF/LEF to activate Wnt-related fibrotic genes. In the Wnt signaling, MAP4K and TAOK families of kinases phosphorylate and activate LATS1/2. Meanwhile, YAP activity is regulated by the LATS1/2 kinases, which promote YAP nucleus accumulation and bind to several transcription factors, such as the TEAD family, eventually changing profibrotic gene expression. In the PI3K-Akt signaling, PI3Ks can be activated by various growth factors like VEGF, PDGF, and TGF-β. The common downstream of receptor-mediated PI3K activation is Akt, which regulates the activity of mTOR, HIF-1α, and Fox3 to involve cell proliferation, differentiation, and ECM deposition in PF. Image Created in https://BioRender.com

Fig. 4

Drug delivery strategies for PF treatment. Drug delivery strategies of various therapeutic modalities (including nanoparticle delivery system, cell-mediated delivery system, and adeno-associated virus vectors-mediated delivery system) for the treatment of PF. Image Created in https://BioRender.com