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. 2022 Aug 29;11(9):1685. doi: 10.3390/antiox11091685

Table 1.

Potential therapies and Nrf2 activators for the treatment of pulmonary fibrosis.

Compound Model Target Function and Detection Index Refs
Rapamycin1 PQ-treated male rats and LFs Nrf2 activating Suppressed PQ-induced oxidant stress, cell death and apoptosis, fibrosis-related factors, reversed PQ-induced FMD and PF induced by PQ. [61]
Tanshinone IIA2 Silica-treated silicosis rat and NIH-3T3 cells TGFβ1/Smad
Nrf2/ NOX4
Nrf2/GSH		 Reduced the levels of collagen deposition, TGF-β1, α-SMA, Col-I, Col-III, NOX4, ROS; increased the levels of Nrf2, HO−1, NQO1, Gclc, Gclm, and GSH; regulated myofibroblast activation, protected Nrf2 from protein ubiquitination, promoted Keap1 degradation. [113,114,115]
Pterostilbene3 Lps-treated female BALB/C mice Nrf2 activating Decreased lung injury and fibrosis scores; reduced levels of Col-I, TGF-β1, HYP, IL-1β, IL-6, TNF-α; increased the levels of Nrf2, HO−1, NQO1, GSH, SOD. [64]
Sinapic acid4 BLM-treated SD rats Nrf2/HO−1
NF-κB		 Increased the levels of Nrf2, inflammatory cell population, GPx, CAT, Bcl-2; reduced the levels of MDA, TNF-α, IL-1β, MPO, MMP-7, HYP, TGF-β1, NF-κB; restore the antioxidant system, inflammatory or fibrotic alterations. [96]
Thymoquinone5 BLM-treated Wistar rats Nrf2/HO−1 Decreased levels of HYP, LDH, total and differential leukocytes, MDA, TNF-α, IL-1β, MPO, MMP-7, caspase-3, Bax, NF-κB; upregulate Nrf2, HO−1, Bcl2; ameliorated severe hemorrhage, thickening of alveolar septa, emphysema, infiltration of leukocytes in walls alveoli and fibroplasia, inflammation, and PF. [99]
Dihydroartemisinin6 BLM-treated SD rats and AECs Nrf2/HO−1 Reduced the levels of α-SMA, MDA; increased the levels of E-cadherin, Nrf2, HO−1, SOD, and GSH; mitigated alveolitis severity, relieved fibrosis scores, inhibited the increase in the myofibroblasts–like processes of the AECs. [100]
Atractylenolide III7 BLM-treated SD rats Nrf2/NQO1/HO−1 Reduced the expression of Caspase-3 and Caspase-9, IL-6, iNOS, TNF-α, MDA, LDH; upregulated the levels of Nrf2, NQO1, HO−1, SOD, GSH, IL-10; improved lung function alleviated PF and oxidative stress. [101]
Rosavin8 BLM-treated Kunming mice Nrf2/NF-κB
TGF-β1		 Inhibited inflammatory cells, MDA, HYP, NF-κB-p65, α-SMA TGF-β1 levels; improved Nrf2, SOD, GSH-Px levels; ameliorated PF, alveolar inflammatory cell contents. [121]
Vitamin D39 Particles-treated Nrf2+/+ and Nrf2−/− C57BL/6 mice, HFLIII cells Nrf2 activating Reduced the levels of α-SMA, FN, E-cadherin; increased the levels of N-cadherin, Nrf2, VDR; limited fibroblast cells’ migration, FDM, ECM. [122]
S-Allylmercaptocysteine10 BLM-treated C57/BL6 mice Nrf2/NOX4
TGF-β1/Smad		 Increased antioxidants such as HO−1, GSH, and SOD; decreased HYP, SMA; ameliorated the pathological structure, and decrease inflammatory cell infiltration and pro-inflammatory cytokines in BALF. [131]
Gallic acid derivative (GAD)11 BLM-treated C57/BL6 mice Nrf2/NOX4
TGF-β1/Smad		 Reduced the levels of α-SMA, HYP, collagen type I/III, IL-6, TGF-β1, NOX4; increase the levels of SOD and GSH; increased body weight, survival rate, and alleviated alveolar structure, alveolar inflammation, and the degree of PF. [132]
Salvia miltiorrhiza12 BLM-treated C57/BL6 mice and NIH-3T3 cells Nrf2/GSH
Nrf2/Keap1
Nrf2/Nox4		 Reduced the levels of TGF-β1, α-SMA, ECM, COL-1, NOX4, ROS, PKC-δ, Smad3; increase the levels of Nrf2, NQO1, HO−1; protected Nrf2 from protein ubiquitination, PF; regulated myofibroblasts activation, Increased the sensitivity of fibroblasts to the loss of GSH. [133]
Dimethyl itaconate13 TGF-β1-induced FMD in vitro and BLM-treated mouse Nrf2 activating Nrf2 decreased TXNIP expression and alleviated FMD in PF; Nrf2 inhibited TGF-β1-induced FMD and the increase of ROS. [141]
Sulforaphane14 BLM-treated C57/BL6 mice Nrf2 activating Reduced the levels of caspase-3, IL-1β, TNF-α, TGF-β, HYP, 3-NT, and 4-HNE; increased the levels of Nrf2, HO−1, NQO1, SOD1, and CAT; alleviated BLM-induced alveolar epithelial cell apoptosis, alveolitis, collagen accumulation, lung oxidative stress, and lung fibrosis. [168]
Bletilla striata15 SiO2-treated C57BL/6 mice and A549 cells line Nrf2/HO−1/γ-GCSc Reduced the levels of MDA, ROS; increased the levels of γ-GCSc, Nrf2, SOD, HO−1; protective effect of lung injury, lung cell viability, apoptosis, and ROS accumulation. [10]
Sarcodon aspratus16 BLM-treated Kunming mice and A549 cells MAPK/Nrf2/HO−1
TGF-β1/MAPK
TLR4/NF-κB		 Reduced the levels of ROS, MDA, TNF-α, IL-1β, IL-6, CTGF, MMP-2, HYP, α-SMA, ECM, TLR4, MyD88, NF-κB-p65; increased the levels of GSH-Px, SOD, Nrf2, HO−1, CAT, Smad7; inhibited H2O2-induced cell apoptosis, oxidative stress, fibrosis, phosphorylation of JNK, ERK and P38, weight loss. [169]
Arenaria kansuensis17 PQ-treated C57BL mice TGF-β1/Smad
NF-κB-p65
Nrf2/NOX4		 Downregulated α-SMA, TGF-β1, TNF-α, IL-6, IL-1β1, HYP, ROS, collagen deposition, NOX4; upregulate Nrf2, SOD, and GSH; improved mice survival rate, body weight, lung pathological lesion, and the lung index. [170]
Quercetin18 BLM-treated BEAS-2B cells Nrf2 activating Reduced the expression levels of ROS, TNF-α, and IL-8; increased Nrf2-ARE binding, HO−1, and γ-GCS; restored the disturbed redox balance and reduce inflammation. [171]
Chelerythrine19 BLM-treated C57/BL6 mice Nrf2/ARE Reduced the expression levels of fibronectin, α-SMA, TGF-β, 4-HNE, and HYP; upregulated the levels of SOD, GSH, Nrf2, HO−1, and NQO1; alleviates collagen deposition, oxidative stress, and PF. [172]
Bergenin20 BLM-treated C57/BL6 mice and NIH3T3 cells p62/Nrf2 Decreased content of α-SMA, COL-1, HYP, ROS, MDA; increased the levels and activity of Nrf2, GSH, SOD, HO−1, NQO1; inhibited the TGF-β1 induced FDM, oxidative stress, and PF. [173]
Jinshui Huanxian formula21 BLM-treated SD rats, MRC-5 cells and NIH-3T3 cells Nrf2/NOX4
TGF-β1		 Reduced the levels of TGF-β1, collagen deposition, HYP, α-SMA, COL-I, COL-III, MDA, MPO, NOX4, FN1; increased the levels of Nrf2, GSH, SOD, CAT, NQO1, HO−1; suppressed the increases of lung coefficient, TGF-β1-induced FDM, ROS production [174]
Dimethyl fumarate22 BLM-treated C57/BL6 mice; RAW264.7 and NIH-3T3 cells coculture Nrf2 activating Attenuated macrophage activity and fibrosis in mice; promoted Nrf2 and HO−1 expression and suppress TGF-β and ROS production; reduced fibroblast-to-myofibroblast transition and collagen production by NIH-3T3 cells. [175]
Chloroquine23 PQ-treated male C57BL/6 mice Nrf2/NQO1/HO−1
TGF-β		 Reduced the levels of TNF-α, IL-1β, IL-6, NO, iNOS, MDA, α-SMA, TGF-β; increased the levels of SOD, NQO1, Nrf2, HO−1; attenuated lung injury, oxidative stress, decreases protein, inflammatory cells. [176]
Esomeprazole24 BLM- or TGF-β-treated PHLE cells and fibroblasts MAPK/Nrf2/HO−1 DDAH/iNOS Reduced the levels of DDAH, iNOS, IL-1β, IL-6, TNF-α, COL-I, COL-III, COL-V; increased the levels of HO−1, NQO1, Nrf2; downregulates pro-inflammatory and profibrotic molecules, collagen expression; activates MAPK via phosphorylation. [156]

The superscript number in the upper right corner of the compounds is numbered according to the order in which the compounds first appeared in the main text.