Lee A Ryang, Jeong Mini, Koo Kyomoon, Kim Sin-Jeong, Pyo Min Ju, Hong Yeeun, Ha Yura, Moon Keun-Ai, Shim Hyun Jae, Lee Ji-Hyang, Kwon Hyouk-Soo, Cho You Sook
Division of Allergy and Clinical Immunology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Allergy. 2025 Mar;80(3):703-714. doi: 10.1111/all.16362. Epub 2024 Oct 27.
Air 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.
To investigate the role of PGRN and its derivatives in the regulation of responses to DEP exposure in allergic airway inflammation.
A 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.
DEP 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.
FBAC 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.
空气污染物，如柴油废气颗粒（DEP），会导致中性粒细胞浸润从而加剧呼吸道疾病。颗粒蛋白前体（PGRN）是一种上皮细胞和巨噬细胞衍生的分泌蛋白，与中性粒细胞炎症相关。PGRN在炎症部位被消化成各种衍生物，并参与多种炎症过程。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。
研究PGRN及其衍生物在调节过敏性气道炎症中对DEP暴露反应的作用。
在PGRN缺陷小鼠中建立过敏性气道炎症小鼠模型，同时使其暴露于DEP，随后经鼻给予全长重组PGRN（PGRN-FL）和一种PGRN衍生片段（FBAC）。通过支气管肺泡灌洗和组织病理学分析评估炎症状态。用DEP和屋尘螨（HDM）刺激人支气管上皮细胞，并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估FBAC处理的效果。
在小鼠模型中，DEP暴露加剧了中性粒细胞炎症，增强了白细胞介素-6（IL-6）和CXC趋化因子配体15（CXCL15）的分泌，并增加了氧化应激；PGRN缺陷小鼠的这种效应比野生型小鼠更明显。接受PGRN-FL治疗的DEP暴露小鼠的中性粒细胞浸润无变化，肺部氧化应激状态更高。相反，给予FBAC可抑制中性粒细胞浸润并降低氧化应激。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的分泌。还观察到核因子红细胞2相关因子2（Nrf2）表达降低，磷酸化p62和微管相关蛋白轻链3β（LC3B）表达增加。FBAC处理减轻了DEP和HDM暴露引起的氧化应激。
在过敏性气道炎症小鼠模型中，FBAC通过降低氧化应激减轻了DEP暴露所加剧的中性粒细胞炎症。PGRN及其衍生蛋白可能是减轻空气污染物暴露所致哮喘加重的新型治疗药物。
