Aims

Acute lung injury (ALI) is triggered by an acute inflammatory response. Lipopolysaccharide (LPS) is recognized as an important participant in the pathogenesis of sepsis, which may induce ALI. N-phenethyl-5-phenylpicolinamide (N5P) is a newly synthesized HIF-1α inhibitor. The purpose of the present study was to investigate the potential protective effects of N5P on LPS-induced ALI and the underlying mechanisms.

Main methods

In vivo experiment, the ALI rat model was induced by intratracheal injection of LPS, and various concentrations of N5P were injected intraperitoneally before LPS administration. In vitro experiment, RAW264.7 macrophages were administrated LPS and N5P to detect inflammatory cytokine changes. HIF-1α overexpression plasmid (HIF1α-OE) and granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycolysis agonist, were used to examine the relationship between the HIF-1α/glycolysis/ASIC1a pathway.

Key findings

Pretreatment with N5P inhibited not only the histopathological changes that occurred in the lungs but also lung dysfunction in LPS-induced ALI. N5P also decreased the levels of lactic acid in lung tissue and arterial blood, and inflammatory factors IL-1β and IL-6 levels in serum. LPS increased HIF-1α, glycolysis proteins GLUT1, HK2, ASIC1a, IL-1β, IL-6, and these changes were reversed by N5P in primary alveolar macrophages and RAW264.7 macrophages. Overexpression of HIF-1α significantly increased glycolysis genes and ASIC1a as well as inflammatory cytokines. Excessive glycolysis levels weaken the ability of N5P to inhibit inflammation.

Significance

N5P may alleviate inflammation in ALI through the HIF-1α/glycolysis/ASIC1a signaling pathway. The present findings have provided pertinent information in the assessment of N5P as a potential, future therapeutic drug for ALI.

中文翻译：

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N-苯乙基-5-苯基吡啶酰胺通过抑制HIF-1α/糖酵解/ASIC1a通路减轻急性肺损伤炎症

目标

急性肺损伤 (ALI) 由急性炎症反应引发。脂多糖（LPS）被认为是脓毒症发病机制的重要参与者，可能诱发ALI。N-phenethyl-5-phenylpicolinamide (N5P) 是一种新合成的 HIF-1α 抑制剂。本研究的目的是研究 N5P 对 LPS 诱导的 ALI 的潜在保护作用及其潜在机制。

主要方法

体内实验采用气管内注射LPS诱导ALI大鼠模型，LPS给药前腹腔注射不同浓度的N5P。在体外实验中，RAW264.7巨噬细胞被给予LPS和N5P以检测炎性细胞因子的变化。HIF-1α过表达质粒（HIF1α-OE）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）是一种糖酵解激动剂，用于检查HIF-1α/糖酵解/ASIC1a通路之间的关系。

主要发现

N5P 预处理不仅抑制了肺中发生的组织病理学变化，而且抑制了 LPS 诱导的 ALI 的肺功能障碍。N5P 还降低了肺组织和动脉血中的乳酸水平，以及血清中炎症因子 IL-1β 和 IL-6 的水平。LPS 增加 HIF-1α、糖酵解蛋白 GLUT1、HK2、ASIC1a、IL-1β、IL-6，并且这些变化在原代肺泡巨噬细胞和 RAW264.7 巨噬细胞中被 N5P 逆转。HIF-1α 的过表达显着增加了糖酵解基因和 ASIC1a 以及炎性细胞因子。过多的糖酵解水平会削弱 N5P 抑制炎症的能力。

意义

N5P 可通过 HIF-1α/糖酵解/ASIC1a 信号通路缓解 ALI 的炎症。目前的研究结果为评估 N5P 作为一种潜在的、未来的 ALI 治疗药物提供了相关信息。