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Abstract：
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood.
OBJECTIVE: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation.
METHODS: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro.
RESULTS: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts.
CONCLUSIONS: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab\'s therapeutic efficacy in AERD.
OBJECTIVE: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation.
METHODS: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro.
RESULTS: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts.
CONCLUSIONS: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab\'s therapeutic efficacy in AERD.
摘要：
背景：阿司匹林加剧的呼吸系统疾病（AERD）是一种涉及2型炎症失调的严重疾病。然而,其他炎症途径在AERD中的作用尚不清楚.
目的：我们试图广泛定义AERD患者上呼吸道的炎症环境，并确定IL-4Rα抑制对鼻腔炎症介质的影响。
方法：对22例接受dupilumab治疗3个月的AERD患者进行3次随访，并与10例健康对照进行比较。使用OlinkTarget48评估鼻液中45种细胞因子和趋化因子。血液中性粒细胞和培养的人肥大细胞，单核细胞/巨噬细胞，和鼻成纤维细胞在体外评估对IL-4/13刺激的反应。
结果：在测量的鼻液细胞因子中，与健康对照组相比，AERD患者中的近三分之一更高，包括IL-6和IL-6家族相关细胞因子制瘤素M（OSM），两者都与鼻白蛋白水平相关，上皮屏障失调的标志。Dupilumab显着减少许多鼻介质，包括OSM和IL-6。IL-4刺激诱导肥大细胞和巨噬细胞产生OSM，但不是来自中性粒细胞，和OSM和IL-13刺激诱导鼻成纤维细胞产生IL-6。
结论：除了2型炎症，先天性和IL-6相关的细胞因子也在AERD的呼吸道中升高。OSM和IL-6均在鼻息肉中局部产生，并可能通过负面影响上皮屏障功能来促进病理。IL-4Rα阻断,虽然看似针对2型炎症，也减少先天炎症和上皮失调的介质，这可能有助于dupilumab在AERD中的治疗效果。
目的：我们试图广泛定义AERD患者上呼吸道的炎症环境，并确定IL-4Rα抑制对鼻腔炎症介质的影响。
方法：对22例接受dupilumab治疗3个月的AERD患者进行3次随访，并与10例健康对照进行比较。使用OlinkTarget48评估鼻液中45种细胞因子和趋化因子。血液中性粒细胞和培养的人肥大细胞，单核细胞/巨噬细胞，和鼻成纤维细胞在体外评估对IL-4/13刺激的反应。
结果：在测量的鼻液细胞因子中，与健康对照组相比，AERD患者中的近三分之一更高，包括IL-6和IL-6家族相关细胞因子制瘤素M（OSM），两者都与鼻白蛋白水平相关，上皮屏障失调的标志。Dupilumab显着减少许多鼻介质，包括OSM和IL-6。IL-4刺激诱导肥大细胞和巨噬细胞产生OSM，但不是来自中性粒细胞，和OSM和IL-13刺激诱导鼻成纤维细胞产生IL-6。
结论：除了2型炎症，先天性和IL-6相关的细胞因子也在AERD的呼吸道中升高。OSM和IL-6均在鼻息肉中局部产生，并可能通过负面影响上皮屏障功能来促进病理。IL-4Rα阻断,虽然看似针对2型炎症，也减少先天炎症和上皮失调的介质，这可能有助于dupilumab在AERD中的治疗效果。
