囊性纤维化中性粒细胞功能障碍。
Neutrophil dysfunction in cystic fibrosis.
机构信息
Massachusetts General Hospital, Department of Pediatrics, Pulmonary Division, Boston, MA, United States; Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, MA, United States; Harvard Medical School, Department of Pediatrics, Boston, MA, United States.
Massachusetts General Hospital, Center for Engineering in Medicine, Boston, MA, United States; Shriners Hospital for Children, Boston, MA, United States.
出版信息
J Cyst Fibros. 2021 Nov;20(6):1062-1071. doi: 10.1016/j.jcf.2021.01.012. Epub 2021 Feb 13.
BACKGROUND
Excessive neutrophil inflammation is the hallmark of cystic fibrosis (CF) airway disease. Novel technologies for characterizing neutrophil dysfunction may provide insight into the nature of these abnormalities, revealing a greater mechanistic understanding and new avenues for CF therapies that target these mechanisms.
METHODS
Blood was collected from individuals with CF in the outpatient clinic, CF individuals hospitalized for a pulmonary exacerbation, and non-CF controls. Using microfluidic assays and advanced imaging technologies, we characterized 1) spontaneous neutrophil migration using microfluidic motility mazes, 2) neutrophil migration to and phagocytosis of Staphylococcal aureus particles in a microfluidic arena, 3) neutrophil swarming on Candida albicans clusters, and 4) Pseudomonas aeruginosa-induced neutrophil transepithelial migration using micro-optical coherence technology (µOCT).
RESULTS
Participants included 44 individuals: 16 Outpatient CF, 13 Hospitalized CF, and 15 Non-CF individuals. While no differences were seen with spontaneous migration, CF neutrophils migrated towards S. aureus particles more quickly than non-CF neutrophils (p < 0.05). CF neutrophils, especially Hospitalized CF neutrophils, generated significantly larger aggregates around S. aureus particles over time. Hospitalized CF neutrophils were more likely to have dysfunctional swarming (p < 0.01) and less efficient clearing of C. albicans (p < 0.0001). When comparing trans-epithelial migration towards Pseudomonas aeruginosa epithelial infection, Outpatient CF neutrophils displayed an increase in the magnitude of transmigration and adherence to the epithelium (p < 0.05).
CONCLUSIONS
Advanced technologies for characterizing CF neutrophil function reveal significantly altered migratory responses, cell-to-cell clustering, and microbe containment. Future investigations will probe mechanistic basis for abnormal responses in CF to identify potential avenues for novel anti-inflammatory therapeutics.
背景
中性粒细胞炎症过度是囊性纤维化（CF）气道疾病的标志。用于描述中性粒细胞功能障碍的新技术可能深入了解这些异常的本质，揭示出对这些机制的更深入的机械理解和针对这些机制的 CF 治疗的新途径。
方法
从门诊诊所的 CF 个体、因肺部恶化而住院的 CF 个体和非 CF 对照者中采集血液。使用微流控分析和先进的成像技术，我们描述了 1）使用微流控运动迷宫的自发中性粒细胞迁移，2）中性粒细胞向金黄色葡萄球菌颗粒的迁移和吞噬作用在微流控场中，3）中性粒细胞在白色念珠菌簇上的聚集，以及 4）使用微光学相干技术（µOCT）诱导的铜绿假单胞菌诱导的中性粒细胞跨上皮迁移。
结果
参与者包括 44 人：16 名门诊 CF 患者，13 名住院 CF 患者和 15 名非 CF 个体。虽然在自发迁移中没有差异，但 CF 中性粒细胞向金黄色葡萄球菌颗粒的迁移速度快于非 CF 中性粒细胞（p<0.05）。随着时间的推移，CF 中性粒细胞，尤其是住院 CF 中性粒细胞，在金黄色葡萄球菌颗粒周围形成的聚集体明显更大。住院 CF 中性粒细胞更有可能出现功能失调的聚集（p<0.01），并且清除白色念珠菌的效率较低（p<0.0001）。在比较朝向铜绿假单胞菌上皮感染的跨上皮迁移时，门诊 CF 中性粒细胞表现出迁移和粘附到上皮的幅度增加（p<0.05）。
结论
用于描述 CF 中性粒细胞功能的先进技术揭示了明显改变的迁移反应、细胞间聚集和微生物容纳。未来的研究将探究 CF 中异常反应的机制基础，以确定新型抗炎治疗的潜在途径。
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