Bertolini Francesca, Carriero Vitina M A, Arrigo Elisa, Guida Giuseppe, Levra Stefano, Pizzimenti Stefano, Profita Mirella, Gnemmi Isabella, Di Stefano Antonino, Ricciardolo Fabio L M
Department of Clinical and Biological Sciences, University of Turin, Turin, TO, Italy.
Rare Lung Disease and Respiratory Pathophysiology Unit, Severe Asthma, San Luigi Gonzaga University Hospital, Orbassano, Turin, TO, Italy.
Respir Res. 2025 Feb 28;26(1):78. doi: 10.1186/s12931-025-03133-9.
Asthma with neutrophilic/mixed inflammation is a difficult-to-control clinical phenotype. Currently, vascular and matrix airway remodeling in asthma with neutrophilic/mixed inflammation is not well known. We aimed to evaluate the differences in vascular/smooth muscle/matrix related asthma remodeling in eosinophilic (EOS) and mixed/neutrophilic (MIXED) bronchial phenotypes in relation to asthma severity and exacerbation frequency.
In this cross-sectional study, α-SMA cells (100µM beneath the basement membrane [BM]), BM thickness, vascular remodeling-related biomarkers (angiogenin, vascular endothelial growth factor [VEGF], CD31 and Protease-activated receptor 2 [PAR2]), alarmins (TSLP and Interleukin (IL)-33) were evaluated in bronchial sections from 40 mild-to-severe asthmatics (EOS: N = 19 and mixed/neutrophilic: N = 19/2) and 7 control subjects (CTRL).
The number of CD31 and angiogenin cells was higher in MIXED than in EOS asthmatics (p < 0.05). In severe MIXED CD31, TSLP, α-SMA, and angiogenin cells increased compared to mild MIXED/EOS or severe EOS (p < 0.05), but BM thickness was higher in severe vs. mild EOS (p < 0.05). MIXED frequent exacerbators had higher numbers of CD31 and TSLP cells, whereas MIXED non-exacerbators had increased PAR2 cells. CD31 cells correlated with impairment of pulmonary functions, number of exacerbations, ICS dose, bronchial neutrophils, angiogenin, α-SMA, TSLP and IL-33 (p < 0.05). Finally, CD31 > 97.17 cells/mm, angiogenin > 35.36 cells/mm, and functional parameters such as FEV, FEV/FVC, TLC and FRC (%pred.) were found to be predictors of severe MIXED asthma.
The severe or frequent exacerbator asthmatics with bronchial mixed inflammatory profile are characterized by increased number of vessels and overexpression of TSLP and angiogenin, suggesting a pathogenetic link between mixed eosinophilic and neutrophilic inflammation and vascular remodeling.
伴有嗜中性粒细胞/混合性炎症的哮喘是一种难以控制的临床表型。目前，伴有嗜中性粒细胞/混合性炎症的哮喘中气道血管和基质重塑情况尚不明确。我们旨在评估嗜酸性粒细胞性（EOS）和混合性/嗜中性粒细胞性（MIXED）支气管表型的哮喘患者在血管/平滑肌/基质相关重塑方面的差异，及其与哮喘严重程度和发作频率的关系。
在这项横断面研究中，对40例轻至重度哮喘患者（EOS组：N = 19；混合性/嗜中性粒细胞性组：N = 19/2）和7例对照者（CTRL）的支气管切片进行评估，检测基底膜（BM）下100µM处的α - SMA细胞、BM厚度、血管重塑相关生物标志物（血管生成素、血管内皮生长因子[VEGF]、CD31和蛋白酶激活受体2[PAR2]）、警报素（TSLP和白细胞介素（IL）- 33）。
MIXED组哮喘患者的CD31和血管生成素细胞数量高于EOS组（p < 0.05）。与轻度MIXED/EOS组或重度EOS组相比，重度MIXED组的CD31、TSLP、α - SMA和血管生成素细胞数量增加（p < 0.05），但重度EOS组的BM厚度高于轻度EOS组（p < 0.05）。MIXED组频繁发作患者的CD31和TSLP细胞数量较多，而MIXED组非频繁发作患者的PAR2细胞数量增加。CD31细胞与肺功能损害、发作次数、吸入糖皮质激素（ICS）剂量、支气管嗜中性粒细胞、血管生成素、α - SMA、TSLP和IL - 33相关（p < 0.05）。最后，发现CD31 > 97.17个细胞/mm、血管生成素 > 35.36个细胞/mm以及诸如第一秒用力呼气容积（FEV）、FEV/用力肺活量（FVC）、肺总量（TLC）和功能残气量（FRC）（%预计值）等功能参数是重度MIXED哮喘的预测指标。
具有支气管混合性炎症特征的重度或频繁发作的哮喘患者，其血管数量增加，TSLP和血管生成素过度表达，提示嗜酸性粒细胞和嗜中性粒细胞混合性炎症与血管重塑之间存在发病学联系。
