OXR1 signaling pathway as a possible mechanism of elastase-induced oxidative damage in pulmonary cells: the protective role of ellagic acid

Abstract

Background and objective: Oxidative stress is a process that occurs through free radicals on the cell membranes which causes damage to the cell and intracellular organelles especially mitochondria membranes. H2O2 induced oxidative stress in human cells is of interest in toxicological research since oxidative stress plays a main role in the etiology of several pathological conditions. Neutrophil Elastase (Serine proteinase) is involved in the pathology process of emphysema as a respiratory disease through lung in ammation, and destruction of alveolar walls. The present study investigated the direct oxidative stress effects of Elastase in comparison with H2O2 on human lung epithelial cells (A549 cells) in relation to the generation of reactive oxygen species (ROS) and modulation of oxidation resistance 1 (OXR1) and its downstream pathway using the well-known antioxidant Ellagic acid as an activator of antioxidant genes.Materials and methods: The human pulmonary epithelial cells (A549) were divided into the 9 groups including: Negative control, Positive control (H2O2), Elastase (15, 30, and 60 mU/ml), Ellagic acid (10 μmol/L), and Elastase+Ellagic acid. Cytotoxicity, reactive oxygen spices generation, oxidative stress pro le, level of reactive metabolites, and gene expression of OXR1 and its downstream genes were measured in all groups.Results: The obtained data demonstrated that Elastase exposure caused to oxidative stress damage in a dose-depended manner which was associated with decreases in antioxidant defense system genes.Conversely, treatment with Ellagic acid as a potent antioxidant showed improved antioxidant enzyme activity and content which was in line with the upregulation of OXR1 signaling pathway genes.Conclusions: The present ndings can highlight the novel mechanism underlying the oxidative stress induces by Neutrophil Elastase through OXR1 and related genes. Moreover, the bene t of Ellagic acid on cytoprotection, resulting from its antioxidant properties was documented.

Standardised Sonneratia apetala Buch.-Ham. fruit extract inhibits human neutrophil elastase and attenuates elastase-induced lung injury in mice

“…out of the ten compounds identified by LC-MS/MS, ellagic acid and gallic acid are known to reduce emphysema in mice and rats. Studies conducted by various groups showed that ellagic acid can prevent inflammation and oxidative stress in elastase-induced emphysema model in rat ( Mansouri et al, 2020 ; Sohrabi et al, 2021 ) and reduce oxidative stress in pulmonary cells induced by elastase ( Bayati et al, 2022 ) . Previous reports also show that gallic acid can ameliorate COPD linked lung inflammation and emphysema in mice ( Singla et al, 2020 ; Wu et al, 2022 ).…”

Regulatory T cell and macrophage crosstalk in acute lung injury: future perspectives

“…For example, they secrete many types of proteinases and ROS, which injure alveolar epithelial cells and reduce the levels of surface proteins. Both of them are important for gas exchange [ 70 ]. They also cause blood vessel damages by impairing vessel permeability.…”

“…Polarization towards the proinflammatory M1 phenotype is regulated by many factors. Studies have demonstrated the important roles of suppressor of cytokine signaling 3 (SOCS3), NF-κB and so on in this process [ 70 , 73 ]. In addition, c-Jun N-terminal kinase (JNK) is interesting because it has a dual effect on the polarization of macrophages.…”