Preconditioning with β-hydroxybutyrate attenuates lung ischemia–reperfusion injury by suppressing alveolar macrophage pyroptosis through the SIRT1-FOXO3 signaling pathway

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

FASEB Journal Pub Date : 2024-09-02 DOI:10.1096/fj.202401188R

Fan Lu, Rurong Wang, Yan Cheng, XueHan Li

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Abstract

The complex pathogenesis of lung ischemia–reperfusion injury (LIRI) was examined in a murine model, focusing on the role of pyroptosis and its exacerbation of lung injury. We specifically examined the levels and cellular localization of pyroptosis within the lung, which revealed alveolar macrophages as the primary site. The inhibition of pyroptosis by VX-765 reduced the severity of lung injury, underscoring its significant role in LIRI. Furthermore, the therapeutic potential of β-hydroxybutyrate (β-OHB) in ameliorating LIRI was examined. Modulation of β-OHB levels was evaluated by ketone ester supplementation and 3-hydroxybutyrate dehydrogenase 1 (BDH-1) gene knockout, along with the manipulation of the SIRT1-FOXO3 signaling pathway using EX-527 and pCMV-SIRT1 plasmid transfection. This revealed that β-OHB exerts lung-protective and anti-pyroptotic effects, which were mediated through the upregulation of SIRT1 and the enhancement of FOXO3 deacetylation, leading to decreased pyroptosis markers and lung injury. In addition, β-OHB treatment of MH-S cells in vitro showed a concentration-dependent improvement in pyroptosis, linking its therapeutic benefits to specific cell mechanisms. Overall, this study highlights the significance of alveolar macrophage pyroptosis in the exacerbation of LIRI and indicates the potential of β-OHB in mitigating injury by modulating the SIRT1-FOXO3 signaling pathway.

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通过SIRT1-FOXO3信号通路抑制肺泡巨噬细胞脓毒症，以β-羟丁酸盐为预处理减轻肺缺血再灌注损伤。

我们在小鼠模型中研究了肺缺血再灌注损伤（LIRI）的复杂发病机制，重点研究了热蛋白沉积的作用及其对肺损伤的加剧作用。我们特别研究了肺内热蛋白沉积的水平和细胞定位，发现肺泡巨噬细胞是主要的定位点。VX-765 可抑制热蛋白沉积，从而减轻肺损伤的严重程度，这表明热蛋白沉积在 LIRI 中发挥着重要作用。此外，还研究了β-羟基丁酸盐（β-OHB）在改善 LIRI 方面的治疗潜力。通过补充酮酯和 3-hydroxybutyrate dehydrogenase 1 (BDH-1) 基因敲除，以及使用 EX-527 和 pCMV-SIRT1 质粒转染操纵 SIRT1-FOXO3 信号通路，评估了对β-OHB 水平的调节。结果表明，β-OHB具有肺保护和抗肺脓肿作用，这些作用是通过上调SIRT1和增强FOXO3去乙酰化介导的，从而导致肺脓肿标志物和肺损伤的减少。此外，β-OHB在体外处理MH-S细胞时显示出浓度依赖性的热休克改善，这将其治疗益处与特定的细胞机制联系起来。总之，这项研究强调了肺泡巨噬细胞脓毒症在 LIRI 恶化过程中的重要性，并指出了 β-OHB 通过调节 SIRT1-FOXO3 信号通路减轻损伤的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

FASEB Journal 生物-生化与分子生物学

CiteScore

9.20

自引率

2.10%

发文量

6243

审稿时长

3 months

期刊介绍： The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.