BackgroundAir pollutants, such as diesel exhaust particles (DEPs), induce respiratory disease exacerbation with neutrophilic infiltration. Progranulin (PGRN), an epithelial cell and macrophage‐derived secretory protein, is associated with neutrophilic inflammation. PGRN is digested into various derivatives at inflammatory sites and is involved in several inflammatory processes. PGRN and its derivatives likely regulate responses to DEP exposure in allergic airway inflammation.AimTo investigate the role of PGRN and its derivatives in the regulation of responses to DEP exposure in allergic airway inflammation.MethodsA murine model of allergic airway inflammation was generated in PGRN‐deficient mice, and they were simultaneously exposed to DEP followed by intranasal administration of full‐length recombinant PGRN (PGRN‐FL) and a PGRN‐derived fragment (FBAC). Inflammatory status was evaluated by bronchoalveolar lavage fluid and histopathologic analyses. Human bronchial epithelial cells were stimulated with DEPs and house dust mites (HDMs), and the effect of FBAC treatment was evaluated by assessing various intracellular signaling molecules, autophagy markers, inflammatory cytokines, and intracellular oxidative stress.ResultsDEP exposure exaggerated neutrophilic inflammation, enhanced IL‐6 and CXCL15 secretions, and increased oxidative stress in the murine model; this effect was greater in PGRN‐deficient mice than in wild‐type mice. The DEP‐exposed mice with PGRN‐FL treatment revealed no change in neutrophil infiltration and higher oxidative stress status in the lungs. On the contrary, FBAC administration inhibited neutrophilic infiltration and reduced oxidative stress. In human bronchial epithelial cells, DEP and HDM exposure increased intracellular oxidative stress and IL‐6 and IL‐8 secretion. Decreased nuclear factor erythroid 2‐related factor 2 (Nrf2) expression and increased phosphor‐p62 and LC3B expression were also observed. FBAC treatment attenuated oxidative stress from DEP and HDM exposure.ConclusionsFBAC reduced neutrophilic inflammation exaggerated by DEP exposure in a mouse model of allergic airway inflammation by reducing oxidative stress. PGRN and PGRN‐derived proteins may be novel therapeutic agents in attenuating asthma exacerbation induced by air pollutant exposure.

中文翻译：

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颗粒蛋白前体衍生物可减轻柴油机尾气颗粒暴露引起的肺中性粒细胞浸润


背景空气污染物，如柴油机尾气颗粒 （DEP），会通过中性粒细胞浸润诱发呼吸系统疾病恶化。颗粒蛋白前体 （PGRN） 是一种上皮细胞和巨噬细胞来源的分泌蛋白，与中性粒细胞炎症有关。PGRN 在炎症部位被消化成各种衍生物，并参与多个炎症过程。PGRN 及其衍生物可能调节过敏性气道炎症中对 DEP 暴露的反应。目的研究 PGRN 及其衍生物在过敏性气道炎症中对 DEP 暴露反应的调节作用。方法在 PGRN 缺陷小鼠中生成过敏性气道炎症的小鼠模型，同时暴露于 DEP，然后鼻内给药全长重组 PGRN （PGRN-FL） 和 PGRN 衍生片段 （FBAC）。通过支气管肺泡灌洗液和组织病理学分析评估炎症状态。用 DEPs 和屋尘螨 （HDM） 刺激人支气管上皮细胞，通过评估各种细胞内信号分子、自噬标志物、炎性细胞因子和细胞内氧化应激来评价 FBAC 处理的效果。结果DEP 暴露夸大了小鼠模型中的中性粒细胞炎症，增强了 IL-6 和 CXCL15 分泌，并增加了氧化应激;这种影响在 PGRN 缺陷小鼠中比在野生型小鼠中更大。接受 PGRN-FL 治疗的 DEP 暴露小鼠显示中性粒细胞浸润没有变化，肺部氧化应激状态较高。相反，FBAC 给药抑制了中性粒细胞浸润并减少了氧化应激。 在人支气管上皮细胞中，DEP 和 HDM 暴露增加了细胞内氧化应激以及 IL-6 和 IL-8 分泌。还观察到核因子红细胞 2 相关因子 2 （Nrf2） 表达降低，磷酸 p62 和 LC3B 表达增加。FBAC 治疗减轻了 DEP 和 HDM 暴露的氧化应激。结论FBAC 通过减少氧化应激减少了过敏性气道炎症小鼠模型中因 DEP 暴露而夸大的中性粒细胞炎症。PGRN 和 PGRN 衍生蛋白可能是减轻空气污染物暴露引起的哮喘恶化的新型治疗剂。