严重中性粒细胞性哮喘患者痰中ACE2，TMPRSS2和FURIN基因表达
2021/04/23
摘要
背景：患有严重哮喘的患者死于COVID-19疾病的风险可能更大。病毒附着和入侵宿主细胞需要血管紧张素转化酶2（ACE2）和酶蛋白酶，跨膜蛋白酶丝氨酸2（TMPRSS2）和FURIN。
方法：我们检查了欧洲U-BIOPRED队列的痰，支气管刷检和支气管活检中ACE2，TMPRSS2和FURIN的微阵列mRNA表达。检查了与基因表达水平相关的临床参数和分子表型，包括哮喘严重程度，痰炎症细胞，肺功能，口服皮质类固醇（OCS）使用和转录组相关簇。
结果：与轻度-中度哮喘相比，重度哮喘的痰中ACE2水平显着增加。在多变量分析中，痰中ACE2水平与OCS的使用和男性呈正相关。痰中FURIN水平与中性粒细胞（％）和严重哮喘的存在显著相关。在支气管刷检样本中，TMPRSS2水平与男性和体重指数呈正相关，而FURIN水平与男性和血液中性粒细胞呈正相关。在支气管活检中，TMPRSS2水平与血液中性粒细胞呈正相关。中性粒细胞表型的特点是高的炎症水平活动，表现出痰中的FURIN水平显着高于嗜酸性2型高表达或弱颗粒性粒细胞氧化磷酸化表型。
结论：ACE2和FURIN的水平可能因哮喘的临床或分子表型而异。痰FURIN的表达水平与中性粒细胞浸润和炎症小体活化密切相关。这可能表明在嗜中性严重哮喘中，SARS-CoV-2感染可能会导致更高的发病率和死亡率。
Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma
Kermani NZ, Song WJ, Badi Y, et al.
Abstract
BACKGROUND:Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells.
METHODS:We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels.
RESULTS:ACE2 levels were signifcantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterized by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes
CONCLUSION:Levels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.
背景：患有严重哮喘的患者死于COVID-19疾病的风险可能更大。病毒附着和入侵宿主细胞需要血管紧张素转化酶2（ACE2）和酶蛋白酶，跨膜蛋白酶丝氨酸2（TMPRSS2）和FURIN。
方法：我们检查了欧洲U-BIOPRED队列的痰，支气管刷检和支气管活检中ACE2，TMPRSS2和FURIN的微阵列mRNA表达。检查了与基因表达水平相关的临床参数和分子表型，包括哮喘严重程度，痰炎症细胞，肺功能，口服皮质类固醇（OCS）使用和转录组相关簇。
结果：与轻度-中度哮喘相比，重度哮喘的痰中ACE2水平显着增加。在多变量分析中，痰中ACE2水平与OCS的使用和男性呈正相关。痰中FURIN水平与中性粒细胞（％）和严重哮喘的存在显著相关。在支气管刷检样本中，TMPRSS2水平与男性和体重指数呈正相关，而FURIN水平与男性和血液中性粒细胞呈正相关。在支气管活检中，TMPRSS2水平与血液中性粒细胞呈正相关。中性粒细胞表型的特点是高的炎症水平活动，表现出痰中的FURIN水平显着高于嗜酸性2型高表达或弱颗粒性粒细胞氧化磷酸化表型。
结论：ACE2和FURIN的水平可能因哮喘的临床或分子表型而异。痰FURIN的表达水平与中性粒细胞浸润和炎症小体活化密切相关。这可能表明在嗜中性严重哮喘中，SARS-CoV-2感染可能会导致更高的发病率和死亡率。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Respir Res, 2021, 22(1): 10）
（Respir Res, 2021, 22(1): 10）
Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma
Kermani NZ, Song WJ, Badi Y, et al.
Abstract
BACKGROUND:Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells.
METHODS:We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels.
RESULTS:ACE2 levels were signifcantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterized by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes
CONCLUSION:Levels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.
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PI3Kδ的选择性抑制剂CPL302-253作为吸入治疗和预防哮喘的候选药物的临床前表征
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