1. Monomethyl fumarate attenuates lung Ischemia/Reperfusion injury by disrupting the GAPDH/Siah1 signaling cascade.
- Author
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Wu SY, Chu SJ, Tang SE, Pao HP, Huang KL, and Liao WI
- Subjects
- Animals, Humans, Male, Rats, Fumarates pharmacology, Fumarates therapeutic use, Apoptosis drug effects, Lung pathology, Lung drug effects, Cytokines metabolism, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Oxidative Stress drug effects, Cells, Cultured, Alveolar Epithelial Cells drug effects, Alveolar Epithelial Cells metabolism, Reperfusion Injury drug therapy, Reperfusion Injury metabolism, Signal Transduction drug effects, Acute Lung Injury drug therapy, Acute Lung Injury pathology, Acute Lung Injury metabolism, Rats, Sprague-Dawley
- Abstract
Monomethyl fumarate (MMF), a potent anti-inflammatory agent used to treat multiple sclerosis, has demonstrated efficacy in various inflammatory and ischemia/reperfusion (IR) models; however, its impact on IR-induced acute lung injury (ALI) has not been explored. We investigated, for the first time, whether MMF attenuates lung IR injury through inhibition of the GAPDH/Siah1 signaling pathway. Rats were subjected to IR injury using an isolated perfused lung model, and proximity ligation assays were employed to evaluate the presence and distribution of the GAPDH/Siah1 complex. In vitro studies involved pretreating human primary alveolar epithelial cells (HPAECs) with MMF and/or inducing GAPDH overexpression or silencing, followed by exposure to hypoxia-reoxygenation. The findings revealed significantly reduced lung damage indicators, including edema, proinflammatory cytokines, oxidative stress and apoptosis, in MMF-treated rats. Notably, MMF treatment inhibited GAPDH/Siah1 complex formation and nuclear translocation, indicating that disruption of the GAPDH/Siah1 cascade was the primary cause of these improvements. Our in vitro studies on pretreated HPAECs corroborate these in vivo findings, further strengthening this interpretation. Our study results suggest that the protective effects of MMF against lung IR injury may be attributed, at least in part, to its ability to disrupt the GAPDH/Siah1 signaling cascade, thereby attenuating inflammatory and apoptotic responses. Given these encouraging results, MMF has emerged as a promising therapeutic candidate for the management of lung IR injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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