Thymic stromal lymphopoietin inhibition attenuates pulmonary inflammation and remodeling in an experimental model of asthma–COPD overlap (ACO)

Asthma–COPD overlap (ACO) is a complex clinical entity characterized by persistent airflow limitation with features of both asthma and chronic obstructive pulmonary disease (COPD), including bronchodilator responsiveness and mixed Th2/Th17-mediated inflammation. Despite its clinical significance, effective therapeutic options remain limited. Thymic stromal lymphopoietin (TSLP), an epithelial alarmin, plays a pivotal upstream role in orchestrating airway inflammation, remodeling, and oxidative stress. To investigate the effects of TSLP inhibition in a murine model of ACO and evaluate its impact on airway hyperresponsiveness, inflammation, remodeling, and oxidative stress. Thirty-two BALB/c mice were randomly allocated into four experimental groups: control (SAL and SAL+TSLPi) and disease (ACO and ACO+TSLPi), representing the asthma–COPD overlap (ACO) model. ACO was induced by ovalbumin sensitization combined with intratracheal elastase instillation. A single intranasal dose of TSLP inhibitor was administered. Pulmonary function (Rrs, Raw, Ers, Gtis and His), bronchoalveolar lavage fluid (BALF), histological and immunohistochemical analyses, and ELISA were performed. TSLP inhibition significantly reduced airway resistance and elastance, as well as inflammatory cell infiltration in BALF— including eosinophils, neutrophils, lymphocytes, and macrophages. Lung tissue analysis showed decreased expression of IL-1β, IL-4, IL-5, IL-6, IL-13, IL-17, TSLP and TNF-α in both the airways and alveolar septa. Remodeling markers (MMP-9, MMP-12, TIMP-1, TGF-β), Mean Linear Intercept (Lm) and collagen deposition were attenuated. Oxidative stress markers, including iNOS, 15-F2t-isoprostane, and NF-κB, were also reduced. TSLP blockade mitigated key pathophysiological mechanisms of ACO in a murine model, supporting its potential as a therapeutic target in diseases characterized by mixed Th2/Th17 inflammation.