罗氟米司特通过抑制TNF-α/NF-κB、NLRP3/IL-1β和内质网应激传感器来对抗大剂量地塞米松诱导的脂肪性肝炎、代谢异常和主动脉损伤

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-04-13 DOI:10.1016/j.lfs.2025.123634

Mohammed Fulayyih Aloufi, Sara H. Hazem, Rania R. Abdelaziz, Ghada M. Suddek

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引用次数: 0

摘要

大剂量地塞米松（DEX）用于重症的治疗。然而，糖皮质激素引起的多系统不良反应是阻碍其有效临床应用的障碍。已经采取了各种措施来改善这些并发症，但成效有限。目的探讨磷酸二酯酶-4 （PDE-4）抑制剂罗氟米司特（roflumilast， ROF）对dex诱导的脂肪性肝炎、代谢异常和主动脉变性的有益作用。结果ROF （2.5 mg/kg和5 mg/kg）对大鼠肝脏和主动脉组织病理异常及血清肝酶升高有明显的逆转作用。这种缓解作用可能归因于PDE-4抑制（^ cAMP），随后调节多种效应器。炎症细胞的趋化性（MCP-1）被ROF处理抑制，这与抑制细胞外ROS的产生（MDA和NO）以及恢复细胞抗氧化防御（GSH）有关。DEX攻击与炎症通路的激活相关，包括TNF-α/NF-κB和NLRP3/IL-1β， ROF组显著抑制炎症通路。DEX的氧化应激和炎症通路的激活导致内质网应激（CHOP和PERK）的激活，对受损伤细胞构成更多威胁，然而，幸运的是，ROF治疗抑制了内质网应激传感器的激活，从而使细胞免于不可避免的损伤。经口服糖耐量试验后，右美托芬引起的空腹胰岛素升高、血糖AUC升高等代谢异常均经ROF治疗后明显改善。结论ROF在DEX诱导的脂肪性肝炎大鼠模型中具有保护肝脏和调节代谢的作用。从而提高DEX在各种疾病治疗中的整体疗效和安全性。

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Roflumilast counteracts high-dose dexamethasone-induced steatohepatitis, metabolic abnormalities and aortic injury via inhibiting TNF-α/NF-κB, NLRP3/IL-1β and ER stress sensors

Introduction

High-dose dexamethasone (DEX) is used for management of severe conditions. However, the multisystem adverse effects induced by glucocorticoids represent a hindering stone toward the effective clinical use of such agents. Various initiatives have been taken to ameliorate these complications with limited success.

Aim

The present study aims to explore the beneficial effects of roflumilast (ROF), a phosphodiesterase-4 (PDE-4) inhibitor, to combat DEX-induced steatohepatitis, metabolic abnormalities and aortic degeneration.

Results

The application of ROF (2.5 and 5 mg/kg) has reverted the hepatic and aortic histopathological abnormalities as well as the rise in serum liver enzymes induced by DEX. Such palliative effect is probably attributed to PDE-4 inhibition (↑cAMP) that subsequently regulates multiple effectors. The chemotaxis of inflammatory cells (MCP-1) was inhibited by ROF treatments which was linked to inhibition of extracellular ROS production (MDA and NO) as well as restoration of cellular antioxidant defense (GSH). DEX challenge was associated with activation of the inflammatory pathways including TNF-α/NF-κB and NLRP3/IL-1β that were significantly dampened in the ROF groups. The oxidative stress as well as activation of inflammatory pathways exerted by DEX has contributed to the activation of endoplasmic reticulum stress (CHOP and PERK) posing more threats to the insulted cells, however, fortunately, ROF treatments showed inhibited activation of ER stress sensors and thereby abstaining the cells from inevitable damage. The metabolic abnormalities induced by DEX including elevated fasting insulin and heightened AUC of blood glucose level upon application of oral glucose tolerance test were significantly improved by ROF treatment.

Conclusion

The findings of our study depicted the hepatoprotective and metabolic regulating potentials of ROF in a rat model of DEX- induced steatohepatitis. Thereby, enhancing the overall efficacy and safety of DEX use in management of various disorders.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.