Background

Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma.

Objectives

We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma.

Methods

We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis.

Results

In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1–dependent manner. Furthermore, administration of IL-1β into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1β or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β– or IL-1α–mediated proinflammatory responses and the stimulatory effects of IL-1β on house dust mite (HDM)–induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1β and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1β levels, and lactate content correlated negatively with lung function.

Conclusions

Collectively, these findings demonstrate that IL-1β/inhibitory κB kinase ε signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.

中文翻译：

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IL-1/抑制性 κB 激酶 ε 诱导的糖酵解增强上皮效应功能并促进过敏性气道疾病。

背景

新兴研究表明，糖酵解增强伴随着炎症反应。事实上，我们对糖酵解与过敏性哮喘患者的相关性一无所知。

目标

我们试图确定过敏性哮喘患者的糖酵解是否发生改变，并探讨其在过敏性哮喘发病机制中的重要性。

方法

我们检查了哮喘患者痰液样本和原代人鼻细胞中糖酵解的变化，并使用过敏性哮喘小鼠模型以及原代小鼠气管上皮细胞来评估糖酵解的相关性。

结果

在过敏性哮喘小鼠模型中，肺部以 IL-1 依赖性方式诱导糖酵解。此外，将IL-1β注入气道会刺激乳酸的产生和糖酵解酶的表达，其中气道上皮细胞中乳酸脱氢酶A的显着表达。事实上，将小鼠气管上皮细胞暴露于 IL-1β 或 IL-1α 会导致糖酵解流量、葡萄糖利用、糖酵解基因表达和乳酸产生增加。IL-1β 或 IL-1α 介导的促炎反应以及 IL-1β 对屋尘螨 (HDM) 诱导的气管上皮细胞胸腺基质淋巴细胞生成素和 GM-CSF 释放的刺激作用需要增强的糖酵解。κB 激酶 ε 抑制剂位于 HDM 或 IL-1β 下游，是 HDM 诱导的糖酵解和过敏性气道疾病发病机制所必需的。乳酸脱氢酶 A 的小干扰 RNA 消融可减弱 HDM 诱导的乳酸水平升高并减弱 HDM 诱导的疾病。与健康受试者的细胞相比，哮喘患者的原代鼻上皮细胞本质上产生更多的乳酸。哮喘患者痰上清液中的乳酸含量明显较高，尤其是中性粒细胞含量超过 61% 的哮喘患者。痰液乳酸与IL-1β水平呈正相关，且乳酸含量与肺功能呈负相关。

结论

总的来说，这些发现表明 IL-1β/抑制性 κB 激酶 ε 信号传导在 HDM 诱导的糖酵解和过敏性气道疾病的发病机制中发挥重要作用。