口服糖皮质激素但仍为重症哮喘患者升高的与2型炎症反应无关的血浆蛋白质
2021/11/24
摘要
背景：哮喘表型需要新的生物标志物的发现。
目的；通过对来自两个特征明确的重度(SA)和轻度至中度(MMA)哮喘患者、慢性阻塞性肺病(COPD)受试者和健康对照组(HC)的样本应用新的蛋白质组，确定与哮喘表型相关的血浆生物标志物。
方法：基于抗体的阵列靶向177种蛋白质，主要涉及炎症、脂质代谢、信号转导和细胞外基质相关的通路，应用于U-BIOPRED队列中525名哮喘患者和HC的血浆，以及验证队列 BIOAIR 中142名哮喘和COPD受试者的血浆。口服皮质类固醇(OCS)的效果由BIOAIR中为期两周的安慰剂对照OCS试验确定，并通过与U-BIOPRED中的客观OCS测量相关联来确认。
结果：在U-BIOPRED中，与MMA和HC相比，SA中有110种蛋白质显著不同，且大部分是升高的。在 U-BIOPRED 和 BIOAIR 中，SA 与 MMA 中的 10 种蛋白质均升高（α-1-抗胰凝乳蛋白酶、载脂蛋白-E、补体成分9、补体因子I、巨噬细胞炎症蛋白-3、白细胞介素6、鞘磷脂磷酸二酯酶3、RANK、TGF-β1和谷胱甘肽S-转移酶）。OCS处理降低了大多数蛋白质，但在校正OCS使用后，SA和MMA之间的差异仍然存在。U-BIOPRED蛋白数据的共识聚类产生了与哮喘控制、生活质量、血液中性粒细胞、hsCRP和BMI相关的六个聚类，但与2型炎症生物标志物无关。肥大细胞特异性酶羧肽酶A3是簇分化的主要因素之一。
结论：血浆蛋白质组学小组揭示了以前尚未探索的潜在有用的2型独立生物标志物，并验证了几种与严重哮喘病理生理有关的蛋白质。
Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation
Mikus MS, Kolmert J, Andersson LI, et al.
Abstract:
BACKGROUND: Asthma phenotyping requires novel biomarker discovery.
OBJECTIVE:To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, chronic obstructive pulmonary disease (COPD) subjects and healthy controls (HC).
METHODS:An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HC in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a two-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED.
RESULTS:In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HC. Ten proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, RANK, TGF-β1, and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, hsCRP, and BMI, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation.
CONCLUSIONS:The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers, and validated several proteins with established involvement in the pathophysiology of severe asthma.
背景：哮喘表型需要新的生物标志物的发现。
目的；通过对来自两个特征明确的重度(SA)和轻度至中度(MMA)哮喘患者、慢性阻塞性肺病(COPD)受试者和健康对照组(HC)的样本应用新的蛋白质组，确定与哮喘表型相关的血浆生物标志物。
方法：基于抗体的阵列靶向177种蛋白质，主要涉及炎症、脂质代谢、信号转导和细胞外基质相关的通路，应用于U-BIOPRED队列中525名哮喘患者和HC的血浆，以及验证队列 BIOAIR 中142名哮喘和COPD受试者的血浆。口服皮质类固醇(OCS)的效果由BIOAIR中为期两周的安慰剂对照OCS试验确定，并通过与U-BIOPRED中的客观OCS测量相关联来确认。
结果：在U-BIOPRED中，与MMA和HC相比，SA中有110种蛋白质显著不同，且大部分是升高的。在 U-BIOPRED 和 BIOAIR 中，SA 与 MMA 中的 10 种蛋白质均升高（α-1-抗胰凝乳蛋白酶、载脂蛋白-E、补体成分9、补体因子I、巨噬细胞炎症蛋白-3、白细胞介素6、鞘磷脂磷酸二酯酶3、RANK、TGF-β1和谷胱甘肽S-转移酶）。OCS处理降低了大多数蛋白质，但在校正OCS使用后，SA和MMA之间的差异仍然存在。U-BIOPRED蛋白数据的共识聚类产生了与哮喘控制、生活质量、血液中性粒细胞、hsCRP和BMI相关的六个聚类，但与2型炎症生物标志物无关。肥大细胞特异性酶羧肽酶A3是簇分化的主要因素之一。
结论：血浆蛋白质组学小组揭示了以前尚未探索的潜在有用的2型独立生物标志物，并验证了几种与严重哮喘病理生理有关的蛋白质。
（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）
（Eur Respir J, 2021.）
（Eur Respir J, 2021.）
Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation
Mikus MS, Kolmert J, Andersson LI, et al.
Abstract:
BACKGROUND: Asthma phenotyping requires novel biomarker discovery.
OBJECTIVE:To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, chronic obstructive pulmonary disease (COPD) subjects and healthy controls (HC).
METHODS:An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HC in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a two-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED.
RESULTS:In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HC. Ten proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, RANK, TGF-β1, and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, hsCRP, and BMI, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation.
CONCLUSIONS:The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers, and validated several proteins with established involvement in the pathophysiology of severe asthma.
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