Chen Chongjia C, Buchheit Kathleen M, Lee Pui Y, Brodeur Kailey E, Sohail Aaqib, Cho Laura, Baloh Carolyn H, Balestrieri Barbara, Derakhshan Tahereh, Feng Chunli, Boyce Joshua A, Dwyer Daniel F, Laidlaw Tanya M
Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass.
Department of Medicine, Harvard Medical School, and the Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass.
J Allergy Clin Immunol. 2024 Aug;154(2):458-467.e3. doi: 10.1016/j.jaci.2024.04.020. Epub 2024 May 3.
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.
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.
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.
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.
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.
阿司匹林加重性呼吸系统疾病（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中所起的作用仍知之甚少。
我们试图广泛定义AERD上呼吸道的炎症环境，并确定抑制IL-4Rα对鼻炎症介质的影响。
对22例接受度普利尤单抗治疗3个月的AERD患者进行3次随访，并与10名健康对照者进行比较。使用Olink Target 48检测鼻液中的45种细胞因子和趋化因子。评估血液中性粒细胞以及培养的人肥大细胞、单核细胞/巨噬细胞和鼻成纤维细胞对IL-4/13刺激的体外反应。
在所检测的鼻液细胞因子中，近三分之一在AERD患者中高于健康对照者，包括IL-6和与IL-6家族相关的细胞因子抑瘤素M（OSM），两者均与鼻白蛋白水平相关，鼻白蛋白水平是上皮屏障失调的一个标志物。度普利尤单抗显著降低了许多鼻介质，包括OSM和IL-6。IL-4刺激可诱导肥大细胞和巨噬细胞产生OSM，但不能诱导中性粒细胞产生，而OSM和IL-13刺激可诱导鼻成纤维细胞产生IL-6。
除了2型炎症外，AERD呼吸道中的先天性和IL-6相关细胞因子也升高。OSM和IL-6均在鼻息肉中局部产生，并可能通过对上皮屏障功能产生负面影响而促进病理过程。IL-4Rα阻断虽然看似针对2型炎症，但也可降低先天性炎症和上皮失调的介质，这可能有助于度普利尤单抗在AERD中的治疗效果。
