ABSTRACTBackgroundEotaxins (EOTs), primarily expressed in airway epithelial cells (AECs), act as chemoattractants for eosinophils in asthma pathogenesis. Recent studies have suggested that EOTs have additional functions beyond chemotaxis. However, the distinct roles of EOTs remain incompletely understood.MethodsSerum EOT1, EOT2, myeloperoxidase (MPO), matrix metalloproteinase‐9 (MMP‐9), and tissue inhibitor of metalloproteinase‐1 (TIMP‐1) levels were evaluated by ELISA and serum eosinophil cationic protein (ECP) levels were measured by ImmunoCAP in 79 adult asthmatics. Clinical characteristics were analyzed by inflammatory phenotype, disease severity, and serum EOT1/EOT2 levels. The functions of EOTs were investigated in vitro and ex vivo. For in vivo, EOT1 and EOT2 were intranasally administered to ovalbumin/lipopolysaccharide‐induced asthmatic mice (BALB/c). To assess neutralization effects, anti‐EOT1 or anti‐EOT2 antibodies were intranasally administered.ResultsSerum EOT1 and EOT2 levels were higher in patients with severe asthma (SA) than in those with non‐SA. Serum EOT1 levels were associated with increased blood/sputum eosinophil counts and serum ECP levels, but not significantly correlated with FEV1 (%) values. In contrast, serum EOT2 levels are correlated with higher serum MPO, MMP‐9, and TIMP‐1 levels but lower FEV1 (%). In asthmatic mice, EOT1 increased eosinophil counts and IL‐5 production, whereas EOT2 induced CXCL1 and MMP‐9 production, junctional dysfunction and epithelial‐to‐mesenchymal transition in the lungs, which were attenuated by neutralizing EOTs using each antibody.ConclusionEOT1 promotes T2/eosinophilic inflammation, whereas EOT2 accelerates airway remodeling and lung function decline by activating neutrophils, providing a new insight into the distinct roles of EOTs in the pathogenesis of SA.