MMP12缺陷可减轻薄荷味电子烟联合屋尘螨暴露对肺铁稳态及氧化应激的影响
2025/06/27
摘要
背景：尽管薄荷味电子烟在青少年及年轻群体中广受欢迎，但关于其吸入对哮喘急性加重的肺部效应尚不明确。在肺组织中，由肺泡巨噬细胞和支气管上皮细胞表达分泌的基质金属蛋白酶12（MMP12）在气道重构（严重哮喘的核心特征）中起关键作用。本研究探讨了MMP12在薄荷味电子烟气溶胶暴露联合屋尘螨（HDM）诱发哮喘反应中的作用。
方法：将野生型（WT）和MMP12基因敲除（KO）的幼年雌性小鼠暴露于特征明确的薄荷味电子烟气溶胶环境，随后接受PBS或HDM处理，并从铁代谢、氧化应激反应及肺部炎症角度评估肺部结局。
结果：研究发现薄荷味电子烟气溶胶含有高水平铁元素。这与电子烟+HDM处理的WT小鼠肺铁稳态失衡现象相关，提示机体存在对抗铁介导毒性的防御机制。具体表现为：电子烟+HDM WT小鼠肺组织中铁转运蛋白、铁蛋白、乳铁蛋白及转铁蛋白浓度改变，抗氧化反应元件（ARE）通路激活，以及NAD(P)H醌氧化还原酶1（NQO1）表达上调。此外，尽管中性粒细胞炎症反应减弱，电子烟+HDM WT小鼠中氧化应激诱导型黏蛋白MUC5AC仍显著增加。相比之下，MMP12 KO小鼠对铁诱导的氧化应激反应具有保护作用，突显了MMP12在此模型中的关键角色。
结论：本研究首次通过体内实验证实，铁代谢在富含尼古丁盐铁的电子烟气溶胶毒性机制中发挥核心作用。该发现为理解电子烟相关肺部病理机制提供了重要证据。
MMP12 deficiency attenuates menthol e-cigarette plus house dust-mite effects on pulmonary iron homeostasis and oxidative stress
R. I. Pinkston, M. Schexnayder, Z. Perveen, I. M. Langohr, T. Jelesijevic, A. L. Penn, et al.
Abstract
BACKGROUND:
Little is known regarding the pulmonary effects induced by the inhalation of menthol-flavored e-cigarette aerosols on asthma exacerbation, despite the popularity of these devices and flavors among youth and young adults. In the lungs, matrix metalloproteinase 12 (MMP12) expressed and secreted by both alveolar macrophages and bronchial epithelial cells plays an essential role in airway remodeling, a key feature of severe asthma. In this study, we investigated the role of MMP12 in menthol-flavored e-cigarette aerosol exposures plus house-dust mite (HDM) induced asthmatic responses.
METHODS:
We exposed wild-type (WT) and MMP12 knockout (KO) juvenile female mice to well-characterized menthol-flavored e-cigarette aerosols followed by either PBS or HDM treatment, and evaluated pulmonary outcomes in terms of iron metabolism, oxidative stress responses and pulmonary inflammation.
RESULTS:
We found high levels of iron in the menthol-flavored e-cigarette aerosol. This correlated with e-cigarette + HDM WT mice exhibiting disruption of pulmonary iron metabolism, suggesting a defense mechanism against iron-mediated toxicity. This was evidenced by altered lung protein concentrations of ferroportin, ferritin, lactoferrin, and transferrin, activation of the antioxidant response element (ARE) pathway and up-regulated expression of NQO1 in e-cigarette + HDM WT mice. Further, despite decreased neutrophilic inflammation, MUC5AC, an oxidative stress inducible mucin, was increased in the e-cigarette + HDM WT mice. In contrast, MMP12 KO mice were protected against iron-induced oxidative stress responses, highlighting a crucial role of MMP12 in this model.
CONCLUSION:
These findings revealed in vivo evidence supporting a crucial role for iron metabolism in nicotine salt iron-rich ENDS aerosol toxicity.
背景：尽管薄荷味电子烟在青少年及年轻群体中广受欢迎，但关于其吸入对哮喘急性加重的肺部效应尚不明确。在肺组织中，由肺泡巨噬细胞和支气管上皮细胞表达分泌的基质金属蛋白酶12（MMP12）在气道重构（严重哮喘的核心特征）中起关键作用。本研究探讨了MMP12在薄荷味电子烟气溶胶暴露联合屋尘螨（HDM）诱发哮喘反应中的作用。
方法：将野生型（WT）和MMP12基因敲除（KO）的幼年雌性小鼠暴露于特征明确的薄荷味电子烟气溶胶环境，随后接受PBS或HDM处理，并从铁代谢、氧化应激反应及肺部炎症角度评估肺部结局。
结果：研究发现薄荷味电子烟气溶胶含有高水平铁元素。这与电子烟+HDM处理的WT小鼠肺铁稳态失衡现象相关，提示机体存在对抗铁介导毒性的防御机制。具体表现为：电子烟+HDM WT小鼠肺组织中铁转运蛋白、铁蛋白、乳铁蛋白及转铁蛋白浓度改变，抗氧化反应元件（ARE）通路激活，以及NAD(P)H醌氧化还原酶1（NQO1）表达上调。此外，尽管中性粒细胞炎症反应减弱，电子烟+HDM WT小鼠中氧化应激诱导型黏蛋白MUC5AC仍显著增加。相比之下，MMP12 KO小鼠对铁诱导的氧化应激反应具有保护作用，突显了MMP12在此模型中的关键角色。
结论：本研究首次通过体内实验证实，铁代谢在富含尼古丁盐铁的电子烟气溶胶毒性机制中发挥核心作用。该发现为理解电子烟相关肺部病理机制提供了重要证据。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Respiratory Research 2025 Vol. 26 Issue 1 DOI: ARTN 13510.1186/s12931-025-03213-w）
MMP12 deficiency attenuates menthol e-cigarette plus house dust-mite effects on pulmonary iron homeostasis and oxidative stress
R. I. Pinkston, M. Schexnayder, Z. Perveen, I. M. Langohr, T. Jelesijevic, A. L. Penn, et al.
Abstract
BACKGROUND:
Little is known regarding the pulmonary effects induced by the inhalation of menthol-flavored e-cigarette aerosols on asthma exacerbation, despite the popularity of these devices and flavors among youth and young adults. In the lungs, matrix metalloproteinase 12 (MMP12) expressed and secreted by both alveolar macrophages and bronchial epithelial cells plays an essential role in airway remodeling, a key feature of severe asthma. In this study, we investigated the role of MMP12 in menthol-flavored e-cigarette aerosol exposures plus house-dust mite (HDM) induced asthmatic responses.
METHODS:
We exposed wild-type (WT) and MMP12 knockout (KO) juvenile female mice to well-characterized menthol-flavored e-cigarette aerosols followed by either PBS or HDM treatment, and evaluated pulmonary outcomes in terms of iron metabolism, oxidative stress responses and pulmonary inflammation.
RESULTS:
We found high levels of iron in the menthol-flavored e-cigarette aerosol. This correlated with e-cigarette + HDM WT mice exhibiting disruption of pulmonary iron metabolism, suggesting a defense mechanism against iron-mediated toxicity. This was evidenced by altered lung protein concentrations of ferroportin, ferritin, lactoferrin, and transferrin, activation of the antioxidant response element (ARE) pathway and up-regulated expression of NQO1 in e-cigarette + HDM WT mice. Further, despite decreased neutrophilic inflammation, MUC5AC, an oxidative stress inducible mucin, was increased in the e-cigarette + HDM WT mice. In contrast, MMP12 KO mice were protected against iron-induced oxidative stress responses, highlighting a crucial role of MMP12 in this model.
CONCLUSION:
These findings revealed in vivo evidence supporting a crucial role for iron metabolism in nicotine salt iron-rich ENDS aerosol toxicity.
上一篇：
RNA结合蛋白KSRP可降低模型小鼠哮喘样特征
下一篇：
嗜酸性粒细胞与胸膜巨噬细胞通过12/15-脂氧合酶通路协同调控IL-33诱导的气道炎症
