Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice

Abstract

Lung fibrosis is the primary pathology in idiopathic pulmonary fibrosis and is considered to result from an increase in reactive oxygen species (ROS) levels in alveolar epithelial cells. However, the exact mechanism underlying lung fibrosis remains unclear and there is no effective therapy. The hydroxyl radical (•OH) has the strongest oxidizing potential among ROS. Recently, •OH localized to the cytoplasm (cyto •OH) was reported to induce cellular senescence, while mitochondria-localized •OH (mt •OH) was reported to induce apoptosis. We developed the cyto •OH- and mt •OH-scavenging antioxidants TA293 and mitoTA293 to evaluate the effects of cyto •OH and mt •OH in a bleomycin (BLM)-induced pulmonary fibrosis model. Treatment of BLM-induced pulmonary fibrosis mice with TA293 suppressed the induction of cellular senescence and fibrosis, as well as inflammation in the lung, but mitoTA293 exacerbated these. Furthermore, in BLM-stimulated primary alveolar epithelial cells, TA293 suppressed the activation of the p-ATMser1981/p-p53ser15/p21, p-HRI/p-eIF2ser51/ATF4/p16, NLRP3 inflammasome/caspase-1/IL-1β/IL1R/p-p38 MAPK/p16, and p21 pathways and the induction of cellular senescence. However, mitoTA293 suppressed the induction of mitophagy, enhanced the activation of the NLRP3 inflammasome/caspase-1/IL1β/IL1R/p-p38 MAPK/p16 and p21 pathways, and exacerbated cellular senescence, inflammation, and fibrosis. Our findings may help develop new strategies to treat idiopathic pulmonary fibrosis.

Pulmonary Protein Oxidation and Oxidative Stress Modulation by Lemna minor L. in Progressive Bleomycin-Induced Idiopathic Pulmonary Fibrosis

“…In the BLM-induced IPF model, ROS generation leads to progressive lipid peroxidation, which affects the reductive carbonyl compounds metabolism, DNA damages, increases collagen synthesis, and directly affects the antioxidant defense system [86]. ROS deactivation is performed by endogenous and exogenous antioxidant systems (SOD, CAT and GSH and etc.).…”

“…•− dismutation, and their inability to reduce with oxidative disorders leads to the development of many pathological conditions [9]. Intracellular ROS and OS infiltration after BLM-induced pulmonary fibrosis is performed after the various antioxidants addition [86]. In accordance with previous studies [7], our results also show that the BLM application leads to a statistically significant increase in the parameters of OS damage i.e., increased lipid peroxidation (MDA) and ROS production (Figure 5), along with increased protein carbonylation.…”

A transcriptomics‐based investigation of the mechanism of pulmonary fibrosis induced by nickel oxide nanoparticles

“…Cell migration, positive regulation of cell proliferation, and lung development were basic BP in pulmonary fibrosis 44 . On the basis of the KEGG analysis, combined with relevant references, 45,46 we found many pulmonary fibrosis‐related pathways, such as the MAPK signaling pathway, Wnt signaling pathway, PI3K‐Akt signaling pathway, and Hippo signaling pathway enriched in DE RNAs. This result suggested that DE RNAs affected the development of pulmonary fibrosis through above BP and pathways.…”

Protective effect of luteolin against oxidative stress‑mediated cell injury via enhancing antioxidant systems

“…Excessive ROS can damage cellular molecules, leading to DNA damage, lipid peroxidation and protein oxidation. These processes are key in the development of various diseases, including cancer and lung fibrosis ( 3 – 5 ). Cells contain a range of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and non-enzymatic antioxidants, such as reduced glutathione (GSH), for defense against ROS ( 6 , 7 ).…”