Resveratrol alleviates blast lung injury by modulating the epithelial sodium channel (ENaC) via the PI3K/AKT pathway

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-02-06 DOI:10.1016/j.intimp.2024.113995

Yichun Bai , Chang Ma , Xiaomeng Jing , Jiang Wu , Sanqiao Yao , Linqiang Tian , Xinwen Dong , Zhen An , Wenjie Ren

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Abstract

Blast lung injury (BLI) is a major cause of death in blast injuries, largely due to pulmonary edema. Effective clearance of alveolar fluid is critical for resolving pulmonary edema, with the epithelial sodium channel (ENaC) playing a key role in this process. Resveratrol (RES), a natural compound with known antioxidant and anti-inflammatory properties, has shown promise in treating respiratory diseases. However, its potential protective effects against BLI, particularly through ENaC modulation, remain unclear. In this study, complementary in vivo and in vitro models were used to investigate mechanisms underlying pulmonary edema following a gas explosion. We discovered that RES significantly alleviated BLI by decreasing pulmonary edema, pulmonary index, W/D ratio, oxidative stress, inflammatory cell infiltration, and TNF-α and IL-1β expression levels in rat lung tissue. RES upregulated the expression of ENaC and PI3K/AKT both in rats and in A549 cells. The knockout of the PI3K-p85 gene suppressed RES-induced upregulation of p-AKT and ENaC, reversing protein expression in A549 cells. Altogether, RES shows potential to attenuate blast-induced lung injury by upregulating ENaC, partly through the PI3K/AKT signaling pathway. This study highlights RES as a potential therapeutic agent for BLI and offers new insights into its mechanisms of action.

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白藜芦醇通过PI3K/AKT通路调节上皮钠通道（ENaC），从而减轻母细胞肺损伤。

爆炸性肺损伤（BLI）是爆炸伤致死的主要原因，主要是由于肺水肿造成的。有效清除肺泡液是缓解肺水肿的关键，而上皮钠通道（ENaC）在这一过程中发挥着关键作用。白藜芦醇（RES）是一种天然化合物，具有已知的抗氧化和抗炎特性，在治疗呼吸系统疾病方面前景看好。然而，它对 BLI 的潜在保护作用，特别是通过 ENaC 调节的作用，仍不清楚。在本研究中，我们使用了互补的体内和体外模型来研究煤气爆炸后肺水肿的机制。我们发现 RES 能明显减轻 BLI，降低大鼠肺组织中的肺水肿、肺指数、W/D 比值、氧化应激、炎症细胞浸润以及 TNF-α 和 IL-1β 的表达水平。RES 可上调大鼠和 A549 细胞中 ENaC 和 PI3K/AKT 的表达。PI3K-p85 基因的敲除抑制了 RES 诱导的 p-AKT 和 ENaC 的上调，逆转了 A549 细胞中的蛋白表达。总之，RES显示出通过上调ENaC（部分通过PI3K/AKT信号通路）减轻爆炸诱导的肺损伤的潜力。本研究强调了 RES 作为 BLI 潜在治疗药物的作用，并对其作用机制提出了新的见解。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.