Table 2.
Class I HDAC inhibitors and Class I isoform-selective inhibitors for treatment of pulmonary fibrosis.
| Study | Lung Fibrosis Model | HDAC Inhibition | Effect/Involved Molecules |
|---|---|---|---|
| Korfei et al. (2015) [165] |
Primary IPF fibroblasts |
Valproic acid (VPA) HDAC1, -2 |
H3K27 acetylation, CIP1 ↑, cell proliferation ↓ BIRC5/surviving ↓ collagen-I ↓ HDAC2 ↓ HDAC7 ↓ |
| Conforti et al. (2017) [169] |
TGF-β-treated primary IPF fibroblasts, Bleomycin mouse model |
Romidepsin (FK228) HDAC1, -2 |
In vitro: H3 acetylation, CIP1 ↑ ACTA2 ↓ COL3A1 ↓ LOX ↓ HDAC4 ↓ inhibition of FMD. In vivo: inhibited lung fibrosis, ECM genes ↓ Lox protein ↓ |
| Chen et al. (2021) [170] |
TGF-β-treated A549 cells, Bleomycin mouse model |
Valproic acid HDAC1, -2 |
In vitro and in vivo: SMAD2/3 deactivation, inhibition of EMT |
| Barter et al. (2010) [265] |
TGF-β-treated embryonic mouse fibroblasts |
Entinostat (MS-275) HDAC1, -3; HDAC3 siRNA |
Inhibition of PI3K and ERK pathways Adam12 ↓ Timp1 ↓ |
| Davies et al. (2012) [275] |
TGF-β-treated primary IPF fibroblasts |
Spiruchostatin A HDAC1, -2 |
H3 acetylation, CIP1 ↑ cell proliferation ↓ inhibition of FMD |
| Noguchi et al. (2015) [278] |
TGF-β-treated A549 cells |
Valproic acid HDAC1, -2 |
H3K27 acetylation, partial inhibition of EMT |
| Kabel et al. (2016) [254] |
Bleomycin rat model |
Valproic acid HDAC1, -2 |
attenuation of lung fibrosis, oxidative stress ↓ BALF: IL6 ↓ TGF-β ↓ TNF-α ↓ |
| Kamio et al. (2017) [279] |
TGF-β-treated normal human lung fibroblasts |
Entinostat (MS-275): HDAC1, -3 |
Restoration of ARHGEF3/XPLN (negative regulator of SPARC) ↑ SPARC ↓ |
| Saito et al. (2019) [171] |
TGF-β-treated normal human lung fibroblasts, Bleomycin mouse model |
NCC170 HDAC8 |
In vitro: H3K27 acetylation, restoration of PPARG expression, ECM protein production ↓ In vivo: inhibited lung fibrosis |
| Chen et al. (2021) [258] |
Bleomycin mouse model |
RGFP966 HDAC3 |
H3 acetylation at the Nrf2 promoter, restoration of Nrf2 expression, E-cadherin expression ↑ ECM proteins ↓ |
| Yuan et al. (2020) [273] |
RA-ILD mouse model | HDAC3 siRNA | miR-19a-3p ↑ IL17RA ↓ IL17/IL17RA signalling ↓ Inflammation ↓ attenuation of lung fibrosis |
Definition of abbreviations: IPF: idiopathic pulmonary fibrosis; EMT: epithelial–mesenchymal transition; ECM: extracellular matrix; FMD: fibroblast-to-myofibroblast differentiation; H3: histone H3; RA-ILD: rheumatoid arthritis (RA) associated interstitial lung disease (ILD); siRNA: small interfering RNA; BALF: bronchoalveolar lavage fluid; ↑: upregulation; ↓: downregulation.