RTA408 alleviates lipopolysaccharide-induced acute lung injury via inhibiting Bach1-mediated ferroptosis

Sep 28, 2024International immunopharmacology

RTA408 reduces sudden lung damage caused by bacterial toxin by blocking a cell death process controlled by Bach1

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Abstract

RTA408 significantly ameliorated LPS-induced acute lung injury in mice.

In vivo experiments showed reduced pathological damage and neutrophil infiltration in LPS-induced lung injury after RTA408 treatment.
RTA408 decreased lung edema in murine lung tissues affected by lipopolysaccharide.
LPS administration resulted in ferroptosis in mice, indicated by increased MDA levels and decreased expression of ferroptosis repressors.
RTA408 reversed the alterations associated with ferroptosis in LPS-stimulated cells.
The protective effect of RTA408 was blocked by the ferroptosis inhibitor ferrostatin-1.
Bach1 knockout mice showed reduced lung injury from LPS, and RTA408's protective effect was not evident in these mice.

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The approved traditional Asian medicine RTA408 (Omaveloxolone) has demonstrated potent anti-inflammatory properties in the treatment of Friedreich's ataxia. However, its effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains poorly understood. This study aims to evaluate the effect of RTA408 on LPS-induced ALI and elucidate its underlying mechanisms. In this study, in vivo experiments demonstrated that RTA408 significantly ameliorated LPS-induced mouse ALI, characterized by reduced pathological damage and neutrophil infiltration as well as decreased lung edema of murine lung tissues. Moreover, LPS administration induced ferroptosis in ALI mice, evidenced by increased MDA levels, reduced GSH and SOD activity, and decreased expression of ferroptosis repressors (GPX4 and SLC7A11), whereas RTA408 reversed these changes. Consistently, RTA408 reduced ferroptosis and improved cell damage in LPS-stimulated MLE-12 cells, as evidenced by decreased ROS and MDA levels, increased SOD, GSH activity and ferroptosis repressors expression. Meanwhile, the protective effective of RTA408 on LPS-induced oxidative damage was blocked by ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistic studies demonstrated that RTA408 inhibited the expression and nuclear translocation of Bach1, and the anti-ferroptosis effect was diminished by Bach1 siRNA or Bach1 knockout (Bach1) mice. Furthermore, Bach1mice exhibited attenuated ALI induced by LPS compared to wild-type (WT) mice, and the protective effect of RTA408 on LPS-challenged ALI was not observed in Bach1mice. In conclusion, our data suggested that RTA408 alleviates LPS-induced ALI by interfering Bach1-mediated ferroptosis and might be a novel candidate for LPS-induced ALI/ARDS therapy. -/--/--/-

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RTA408 alleviates lipopolysaccharide-induced acute lung injury via inhibiting Bach1-mediated ferroptosis

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