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The mechanism of itaconic acid alleviating acute lung injury induced by lipopolysaccharide / 中华急诊医学杂志
Chinese Journal of Emergency Medicine ; (12): 1223-1228, 2022.
Article in Chinese | WPRIM | ID: wpr-954544
ABSTRACT

Objective:

To investigate the role and mechanism of exogenous derivative 4-octyl itaconate (4-OI) in lipopolysaccharide (LPS)-induced acute lung injury (ALI).

Methods:

C57BL/6 male mice were randomly divided into the control group, 4-OI group, LPS group, 4-OI+LPS group and deferiprone (DFP)+LPS group, with 6 mice in each group. LPS-induced ALI model was established by intraperitoneal injection of LPS. For the 4-OI+LPS group, mice were pretreated with 4-OI for 2 h before stimulation with LPS. The mice were sacrificed 12 h later and lung tissues were collected for pathological and molecular biological examination. Hematoxylin-eosin and Masson staining were used to detect the level of lung injury and collagen deposition. The expression levels of inflammatory cytokines and ferroptosis associated genes were detected by real-time quantitative PCR, and ferroptosis associated proteins were detected by Western blotting. The chi-square test was performed before the measurement data were counted. One-way analysis of variance was used to compare differences between multiple groups.

Results:

Compared with the control group, the histopathological damage was aggravated, and collagen deposition and lung injury score and lung wet-dry ratio were significantly increased in the LPS group (all P<0.05), and 4-OI pre-treatment significantly alleviated LPS-induced ALI. 4-OI treatment also significantly reduced the mRNA level of inflammatory cytokines, including IL-1β [(4.38±0.47) vs. (32.65±4.49)], IL-6 [(3.97±0.64) vs. (12.22±0.91)] and TNF-α [(15.06±2.26) vs. (38.53±2.31)]. At the same time, compared with the control group, the levels of lipid peroxidation metabolite 4-hydroxynonenal and malondialdehyde, iron level of lung tissue were significantly increased in the LPS group, and the mRNA level of ferroptosis marker prostaglandin-endoperoxide synthase 2 was also significantly increased (all P<0.05), but these indicators were significantly lower in the 4-OI+LPS group than in the LPS group. The results of immunofluorescence, Western blotting and PCR showed that the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH1) significantly decreased in the LPS group, while 4-OI treatment significantly increased the Nrf2, GPX4 and FTH1 levels, and showed similar inhibition of ferroptosis with DFP (all P<0.05).

Conclusions:

4-OI attenuates LPS-induced ALI by increasing Nrf2 and upregulating FTH1 and GPX4, providing a potential drug and its theoretical mechanism for the prevention and treatment of ALI.

Full text: Available Index: WPRIM (Western Pacific) Language: Chinese Journal: Chinese Journal of Emergency Medicine Year: 2022 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Language: Chinese Journal: Chinese Journal of Emergency Medicine Year: 2022 Type: Article