Table 2 The inducers of fibroblast activation and alveolar epithelial cells transformation in the pathogenesis of PF
Type | Inducer | Mechanism of action | Pathway | References |
|---|---|---|---|---|
Fibroblast activation | TGF-β1 | TGF-β1 induced the upregulation of DNMT3a and TET3 expression in fibroblasts↑ | DNA methylation | [55] |
Inhibited PDGFRα or PDGFRβ blunt macrophage infiltration and differentiation into myofibroblasts↓ | PDGFR | [56] | ||
CXCL4 | Boosting myofibroblast differentiation and collagen synthesis↑ | CXCL4 | [57] | |
CCL1 | Recruiting fibroblasts via CCR8↑ Mediating fibroblast activation via AMFR | AMFR-SPRY1 | [58] | |
ECM | Overexpression of YAP, TAZ and glycoprotein fibronectin dictates FMT process↑ | FMT | [59] | |
lncIAPF | Inhibited ELAVL1/HuR dependent autophagy to regulate FMT↓ | ELAVL1/HuR | [60] | |
lncPFAR | Acting as a competing endogenous RNA of miR-138 to promote fibroblasts activation↑ | YAP1-Twist | [61] | |
DNM3OS | Acting as a fibroblast-specific critical downstream effector of TGF-β-induced lung myofibroblast activation↓ | miRNA | [62] | |
Notch3 FAP | Notch3 deficiency mitigates PF via inhibiting myofibroblast activation↓ | Notch3 | [64] | |
α-SMA-positive myofibroblasts increased after Notch3 knockout↓ | Notch3 | [65] | ||
Fibroblast activation | FAP targeted PI3K inhibitor against myofibroblasts activation and collagen deposition↓ | PI3K | [66] | |
Wnt/β-catenin | Enhanced EMT and myofibroblast differentiation↑ | Wnt/β-catenin | [67] | |
Alveolar epithelial cells | TGF-β | Elevated TGF-β promotes the EMT inducers and maintainer, SNAIL-1 and SNAIL-2↑ | TGF-β/SMAD | [68] |
WISP-1 | Upregulation of WISP-1 activates ECM-related cytokines to induce fibrotic process↑ | Wnt/β-catenin | [69] | |
YAP | Transmitting the mechanical tension to fibrotic phenotypes within PF microenvironment↑ | Hippo | [70] | |
Notch1-4 | Notch activity regulates EMT interactions crucial for development and homeostasis of primary AECs↑ | Notch | [71] | |
SASP | Remodel profibrotic microenvironment↑ Enhancing ECM components during fibrosis↑ | AEC senescence | [72] | |
IL-6 | Elevated the expression of p16 and p21 in aged ATII cells↑ | JAK/STAT | ||
IGF-1 | Mediated the expression of p21 andβ-Galactosidase in aged ATII cells after radiation↓ | AEC senescence | [75] |