支气管上皮细胞低CC16 mRNA表达水平与哮喘严重程度相关
2022/10/17
摘要
理由：CC16是一种主要由非纤毛支气管上皮细胞（BEC）产生的蛋白质，参与宿主防御。支气管肺泡灌洗液和血清中CC16蛋白水平降低与哮喘易感性相关。
目的：很少有研究探讨CC16与哮喘进展的关系，也没有研究关注BEC。在这项研究中，我们试图确定BEC中CC16 mRNA表达水平是否与哮喘严重程度相关。
方法：采用广义线性模型对BEC（242名哮喘患者和69名对照）中CC16 mRNA表达水平与严重哮喘研究计划（SARP）中哮喘相关表型之间的关联进行分析。
测量和主要结果：BEC中低CC16 mRNA表达水平与哮喘易感性和哮喘严重程度、高系统性皮质类固醇使用、高回顾性和前瞻性哮喘恶化以及肺功能差显著相关。低CC16 mRNA表达水平与高T2炎症生物标志物（呼出一氧化氮分数（FeNO）和痰嗜酸性粒细胞）显著相关。CC16 mRNA的表达水平与Th2基因的表达水平（IL1RL1、POSTN、SERPINB2、CLCA1、NOS2和MUC5AC）呈负相关，与Th1和炎症基因（IL12A和MUC5B）的表达水平呈正相关。两种非T2生物标记物（CC16和IL-6）的组合揭示了四种哮喘内切型，具有T2炎症、肥胖和哮喘严重程度的不同特征。
结论：我们的研究结果表明，BEC中低CC16 mRNA表达水平与哮喘易感性、严重性和发作相关，部分通过T2炎症的免疫调节。CC16是哮喘发展和进展的潜在非T2生物标记物。
Low CC16 mRNA Expression Levels in Bronchial Epithelial Cells Are Associated with Asthma Severity
Xingnan Li, Stefano Guerra, Julie G Ledford, Monica Kraft, Huashi Li, Annette T Hastie, Mario Castro, Loren C Denlinger, Serpil C Erzurum, John V Fahy, Benjamin Gaston, Elliot Israel, Nizar N Jarjour, Bruce D Levy, David T Mauger, Wendy C Moore, Joe Zein, Naftali Kaminski, Sally E Wenzel, Prescott G Woodruff, Deborah A Meyers, Eugene R Bleecker, NHLBI Severe Asthma Research Program (SARP)
Abstract
Rationale: CC16 is a protein mainly produced by non-ciliated bronchial epithelial cells (BEC) that participates in host defense. Reduced CC16 protein levels in bronchoalveolar lavage and serum are associated with asthma susceptibility.
Objectives: Few studies have investigated the relationship of CC16 and asthma progression, and none has focused on BEC. In this study, we sought to determine if CC16 mRNA expression levels in BEC are associated with asthma severity.
Methods: Association analyses between CC16 mRNA expression levels in BEC (242 asthmatics and 69 controls) and asthma-related phenotypes in the Severe Asthma Research Program (SARP) were performed using a generalized linear model.
Measurements and main results: Low CC16 mRNA expression levels in BEC 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 (FeNO) and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (IL1RL1, POSTN, SERPINB2, CLCA1, NOS2, and MUC5AC), and positively correlated with expression levels of Th1 and inflammation genes (IL12A and MUC5B). A combination of two non-T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity.
Conclusions: Our findings indicate that low CC16 mRNA expression levels in BEC are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential non-T2 biomarker for asthma development and progression.
理由：CC16是一种主要由非纤毛支气管上皮细胞（BEC）产生的蛋白质，参与宿主防御。支气管肺泡灌洗液和血清中CC16蛋白水平降低与哮喘易感性相关。
目的：很少有研究探讨CC16与哮喘进展的关系，也没有研究关注BEC。在这项研究中，我们试图确定BEC中CC16 mRNA表达水平是否与哮喘严重程度相关。
方法：采用广义线性模型对BEC（242名哮喘患者和69名对照）中CC16 mRNA表达水平与严重哮喘研究计划（SARP）中哮喘相关表型之间的关联进行分析。
测量和主要结果：BEC中低CC16 mRNA表达水平与哮喘易感性和哮喘严重程度、高系统性皮质类固醇使用、高回顾性和前瞻性哮喘恶化以及肺功能差显著相关。低CC16 mRNA表达水平与高T2炎症生物标志物（呼出一氧化氮分数（FeNO）和痰嗜酸性粒细胞）显著相关。CC16 mRNA的表达水平与Th2基因的表达水平（IL1RL1、POSTN、SERPINB2、CLCA1、NOS2和MUC5AC）呈负相关，与Th1和炎症基因（IL12A和MUC5B）的表达水平呈正相关。两种非T2生物标记物（CC16和IL-6）的组合揭示了四种哮喘内切型，具有T2炎症、肥胖和哮喘严重程度的不同特征。
结论：我们的研究结果表明，BEC中低CC16 mRNA表达水平与哮喘易感性、严重性和发作相关，部分通过T2炎症的免疫调节。CC16是哮喘发展和进展的潜在非T2生物标记物。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Am J Respir Crit Care Med. 2022 Sep 6. doi: 10.1164/rccm.202206-1230OC.)
(Am J Respir Crit Care Med. 2022 Sep 6. doi: 10.1164/rccm.202206-1230OC.)
Low CC16 mRNA Expression Levels in Bronchial Epithelial Cells Are Associated with Asthma Severity
Xingnan Li, Stefano Guerra, Julie G Ledford, Monica Kraft, Huashi Li, Annette T Hastie, Mario Castro, Loren C Denlinger, Serpil C Erzurum, John V Fahy, Benjamin Gaston, Elliot Israel, Nizar N Jarjour, Bruce D Levy, David T Mauger, Wendy C Moore, Joe Zein, Naftali Kaminski, Sally E Wenzel, Prescott G Woodruff, Deborah A Meyers, Eugene R Bleecker, NHLBI Severe Asthma Research Program (SARP)
Abstract
Rationale: CC16 is a protein mainly produced by non-ciliated bronchial epithelial cells (BEC) that participates in host defense. Reduced CC16 protein levels in bronchoalveolar lavage and serum are associated with asthma susceptibility.
Objectives: Few studies have investigated the relationship of CC16 and asthma progression, and none has focused on BEC. In this study, we sought to determine if CC16 mRNA expression levels in BEC are associated with asthma severity.
Methods: Association analyses between CC16 mRNA expression levels in BEC (242 asthmatics and 69 controls) and asthma-related phenotypes in the Severe Asthma Research Program (SARP) were performed using a generalized linear model.
Measurements and main results: Low CC16 mRNA expression levels in BEC 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 (FeNO) and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (IL1RL1, POSTN, SERPINB2, CLCA1, NOS2, and MUC5AC), and positively correlated with expression levels of Th1 and inflammation genes (IL12A and MUC5B). A combination of two non-T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity.
Conclusions: Our findings indicate that low CC16 mRNA expression levels in BEC are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential non-T2 biomarker for asthma development and progression.
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