背景:乳转铁蛋白(LTF)具有免疫调节功能,其表达水平与哮喘易感性相关。
目的:我们试图研究人支气管上皮细胞(BECs)中作为抗2型(抗T2)哮喘生物标志物的LTFmRNA表达水平。
方法:使用广义线性模型,在重症哮喘研究计划(SARP)横断面(n=155)和纵向(n=156)队列中进行BECs中LTFmRNA表达水平与哮喘相关表型之间的关联分析。使用Spearman相关性进行LTF与所有其他基因之间的mRNA表达水平的相关性分析。
结果:低LTFmRNA表达水平与哮喘易感性和严重程度相关(P<0.025),回顾性和前瞻性哮喘急性发作,肺功能低下(P<8.3x10-3)。低LTFmRNA表达水平与高气道T2炎症生物标志物(痰嗜酸性粒细胞和部分呼出气一氧化氮;P<8.3x10-3)相关,但与血液嗜酸性粒细胞或总血清IgE无关。LTFmRNA表达水平与Th2或哮喘相关基因的表达水平呈负相关(POSTN,NOS2和MUC5AC)和嗜酸性粒细胞相关基因(IL1RL1,CCL26和IKZF2),并与Th1和炎症基因(IL12A,MUC5B,和CC16)和Th17驱动的中性粒细胞细胞因子或趋化因子(CXCL1,CXCL6和CSF3)(P<3.5x10-6)。
结论:BECs中LTFmRNA低表达水平与哮喘易感性相关,严重程度,并通过上调气道T2炎症而加重。LTF是一种潜在的抗T2生物标志物,其表达水平可能有助于确定嗜酸性粒细胞和中性粒细胞哮喘的平衡。
BACKGROUND: Lactotransferrin (LTF) has an immunomodulatory function, and its expression levels are associated with asthma susceptibility.
OBJECTIVE: We sought to investigate LTF messenger RNA (mRNA) expression levels in human bronchial epithelial cells (BECs) as an anti-type 2 (T2) asthma biomarker.
METHODS: Association analyses between LTF mRNA expression levels in BECs and asthma-related phenotypes were performed in the Severe Asthma Research Program (SARP) cross-sectional (n = 155) and longitudinal (n = 156) cohorts using a generalized linear model. Correlation analyses of mRNA expression levels between LTF and all other genes were performed by Spearman correlation.
RESULTS: Low LTF mRNA expression levels were associated with asthma susceptibility and severity (P < .025), retrospective and prospective asthma exacerbations, and low lung function (P < 8.3 × 10-3). Low LTF mRNA expression levels were associated with high airway T2 inflammation biomarkers (sputum eosinophils and fractional exhaled nitric oxide; P < 8.3 × 10-3) but were not associated with blood eosinophils or total serum IgE. LTF mRNA expression levels were negatively correlated with expression levels of TH2 or asthma-associated genes (POSTN, NOS2, and MUC5AC) and eosinophil-related genes (IL1RL1, CCL26, and IKZF2) and positively correlated with expression levels of TH1 and inflammation genes (IL12A, MUC5B, and CC16) and TH17-driven cytokines or chemokines for neutrophils (CXCL1, CXCL6, and CSF3) (P < 3.5 × 10-6).
CONCLUSIONS: Low LTF mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations through upregulation of airway T2 inflammation. LTF is a potential anti-T2 biomarker, and its expression levels may help determine the balance of eosinophilic and neutrophilic asthma.