Division of Genetics, Genomics, and Precision Medicine, and.
Asthma and Airway Disease Research Center, Department of Medicine, University of Arizona, Tucson, Arizona.
Am J Respir Crit Care Med. 2023 Feb 15;207(4):438-451. doi: 10.1164/rccm.202206-1230OC.
CC16 is a protein mainly produced by nonciliated bronchial epithelial cells (BECs) that participates in host defense. Reduced CC16 protein concentrations in BAL and serum are associated with asthma susceptibility. Few studies have investigated the relationship between CC16 and asthma progression, and none has focused on BECs. In this study, we sought to determine if CC16 mRNA expression levels in BECs are associated with asthma severity. Association analyses between CC16 mRNA expression levels in BECs (242 asthmatics and 69 control subjects) and asthma-related phenotypes in Severe Asthma Research Program were performed using a generalized linear model. Low CC16 mRNA expression levels in BECs were significantly associated with asthma susceptibility and asthma severity, high systemic corticosteroids use, high retrospective and prospective asthma exacerbations, and low pulmonary function. Low CC16 mRNA expression levels were significantly associated with high T2 inflammation biomarkers (fractional exhaled nitric oxide and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (, , , , , and ) and positively correlated with expression levels of Th1 and inflammation genes ( and ). A combination of two nontraditional T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity. Our findings indicate that low CC16 mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential nontraditional T2 biomarker for asthma development and progression.
CC16 是一种主要由非纤毛支气管上皮细胞 (BEC) 产生的蛋白，参与宿主防御。BAL 和血清中 CC16 蛋白浓度降低与哮喘易感性相关。很少有研究调查 CC16 与哮喘进展之间的关系，也没有研究关注 BEC。在这项研究中，我们试图确定 BEC 中的 CC16 mRNA 表达水平是否与哮喘严重程度相关。使用广义线性模型对 Severe Asthma Research Program 中 BEC 中的 CC16 mRNA 表达水平（242 名哮喘患者和 69 名对照）与哮喘相关表型之间的关联进行了分析。BEC 中低 CC16 mRNA 表达水平与哮喘易感性和严重程度、高全身皮质激素使用、高回顾性和前瞻性哮喘加重以及低肺功能显著相关。低 CC16 mRNA 表达水平与高 T2 炎症生物标志物（呼气一氧化氮分数和痰嗜酸性粒细胞）显著相关。CC16 mRNA 表达水平与 Th2 基因（、、、、和）的表达水平呈负相关，与 Th1 和炎症基因（和）的表达水平呈正相关。两个非传统 T2 生物标志物（CC16 和 IL-6）的组合揭示了四种具有不同 T2 炎症、肥胖和哮喘严重程度特征的哮喘内型。我们的研究结果表明，BEC 中低 CC16 mRNA 表达水平与哮喘易感性、严重程度和加重有关，部分通过 T2 炎症的免疫调节。CC16 是哮喘发生和进展的潜在非传统 T2 生物标志物。
