Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown etiopathogenesis. The activation of extracellular matrix (ECM)-producing myofibroblasts plays a key role in fibrotic tissue remodeling. The dedifferentiation of myofibroblasts has attracted considerable attention as a promising target for the development of effective therapeutic interventions against IPF. Here, we screened a small library of epigenetics-related inhibitors using dedifferentiation assay of lung myofibroblasts prepared from a patient at the terminal stages of IPF and chose UNC0379. The inhibition of SET8, a histone H4 lysine 20 (H4K20) monomethyltransferase, by UNC0379 markedly suppressed the expression of α-smooth muscle actin (SMA) and ED-A-fibronectin in myofibroblasts. In IPF myofibroblasts, SET8 expression and H4K20 monomethylation (H4K20me1) levels, which were significantly higher than those in normal human lung fibroblasts, were reduced upon treatment with UNC0379. Hence, the changes in the expression of the two fibrotic markers clearly correlated with those in SET8 expression and H4K20me1 level. Furthermore, in a mouse model of bleomycin (BLM)-induced lung fibrosis, the intratracheal administration of UNC0379 at an early fibrotic stage markedly ameliorated the histopathological changes associated with collagen deposition in the lungs. However, treatment with UNC0379 did not significantly affect the number of proinflammatory cells or cytokine production in the bronchoalveolar lavage fluids from mice treated with BLM. In the BLM-injured lung, SET8 was predominantly localized to the nuclei of α-SMA-positive cells, which colocalized with H4K20me1. Taken together, our results indicate that the inhibition of SET8 resulting in myofibroblast dedifferentiation may partly mitigate lung fibrosis without affecting the inflammatory responses.
Highlights
Idiopathic pulmonary fibrosis (IPF) is one of the most common causes of interstitial pneumonia, characterized by progressive and irreversible fibrotic scar formation, resulting in lung malfunction
Some key findings of these studies include: (1) a DNA hypermethylation-associated decrease in mRNA expression was detected for 16 genes in patients with IPF (Sanders et al, 2012) using DNA methylation array and RNA expression microarrays; (2) spiruchostatin A, a histone deacetylase blocker, efficiently reduced the uncontrolled proliferation of IPF fibroblasts (Davies et al, 2012); (3) lysinespecific demethylase 1 contributes to fibroblast to myofibroblast differentiation (FMD) and fibrosis through the TGF-β1/Smad3 signaling pathway (Pan et al, 2020); (4) among non-coding RNAs, miRNAs function as both profibrotic and antifibrotic mediators in IPF (Tzouvelekis and Kaminski, 2015; Rubio et al, 2020)
On the other hand, > 90% of normal human lung fibroblasts (NHLF) were positive for S100 calcium binding protein A4 (S100A4, known as fibroblast-specific protein 1), while the IPF-MyoF showed negligible S100A4 expression
Summary
Idiopathic pulmonary fibrosis (IPF) is one of the most common causes of interstitial pneumonia, characterized by progressive and irreversible fibrotic scar formation, resulting in lung malfunction. Prostaglandin E2, which can dedifferentiate TGF-β1-induced myofibroblasts, fails to revert the phenotype of myofibroblasts from the lungs of patients with IPF (Huang et al, 2010; Garrison et al, 2013) These findings suggest that using IPF lung-derived myofibroblasts is more relevant when screening for antifibrotic agents. Some key findings of these studies include: (1) a DNA hypermethylation-associated decrease in mRNA expression was detected for 16 genes in patients with IPF (Sanders et al, 2012) using DNA methylation array and RNA expression microarrays; (2) spiruchostatin A, a histone deacetylase blocker, efficiently reduced the uncontrolled proliferation of IPF fibroblasts (Davies et al, 2012); (3) lysinespecific demethylase 1 contributes to FMD and fibrosis through the TGF-β1/Smad signaling pathway (Pan et al, 2020); (4) among non-coding RNAs, miRNAs function as both profibrotic and antifibrotic mediators in IPF (Tzouvelekis and Kaminski, 2015; Rubio et al, 2020). Inhibition of SET8 may represent a new therapeutic strategy for tumors and for pulmonary fibrosis
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