Vascular remodeling and TSLP/angiogenin overexpression in severe mixed asthma

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/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.

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.