Vascular remodeling and TSLP/angiogenin overexpression in severe mixed asthma

Background: 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. Methods: 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). Results: 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/mm2, angiogenin > 35.36 cells/mm2, and functional parameters such as FEV1, FEV1/FVC, TLC and FRC (%pred.) were found to be predictors of severe MIXED asthma. Conclusion: 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.