Abstract Rationale Asthma-COPD overlap (ACO) represents a distinct clinical phenotype that shares characteristics of both asthma and chronic obstructive pulmonary disease (COPD). Patients with ACO experience heightened respiratory symptoms, frequent exacerbations, and accelerated lung function decline. Although ACO is estimated to affect approximately 20% of individuals with asthma and 25% with COPD, it lacks defined molecular biomarkers and specific targeted therapies. Identifying circulating biomarkers that differentiate ACO from asthma and COPD is essential for improving diagnosis and guiding treatment. To address this gap, we developed a murine ACO model incorporating key features of both diseases and employed the SOMAscan aptamer-based proteomic platform to characterize its serum proteomic profile. Methods Mice were randomly assigned to four groups: control, asthma, COPD, and ACO. The asthma model was generated by ovalbumin (OVA) sensitization followed by four weeks of OVA aerosol challenge. The COPD model was established by administering two doses of lipopolysaccharide (LPS) combined with six weeks of cigarette smoke exposure. The ACO model combined both OVA sensitization and challenge, as in the asthma group, followed by LPS instillations and cigarette smoke exposure as in the COPD group. Control mice received saline and air exposure only. Serum samples were collected and analyzed using the SOMAscan assay to quantify 1,500 protein analytes. Differential protein expression among groups was assessed using ANOVA, and selected candidate proteins were validated by ELISA. Results The ACO model reproduced key pathological features of both asthma and COPD, including elevated eosinophil and neutrophil counts in bronchoalveolar lavage fluid, pronounced airway inflammation, epithelial hyperplasia, and emphysema-like alveolar enlargement. Proteomic profiling identified 77 proteins with significantly altered expression across experimental groups (p 0.05, fold change ≥ 0.5). Among these three proteins, proliferating cell nuclear antigen (PCNA; DNA replication), AT-rich interaction domain 1A (ARID1A; chromatin remodeling), and filamin-binding LIM protein 1 (FBLIM1; cell adhesion), were uniquely elevated in ACO compared with all other groups. ELISA validation confirmed the highest serum levels of PCNA, ARID1A, and FBLIM1 in ACO, with FBLIM1 significantly increased relative to both asthma and COPD groups. Conclusion This integrated proteomic analysis provides a comprehensive characterization of the ACO plasma proteome and identifies distinct circulating proteins associated with disease overlap. When evaluated alongside established asthma and COPD biomarkers, these biomarkers may enhance differentiation of ACO from asthma and COPD, improving diagnostic precision and guiding targeted therapeutic strategies. Further validation in human serum cohorts is warranted to confirm its clinical relevance. This abstract is funded by: Institutional funds
Folz et al. (Fri,) studied this question.