Chronic Obstructive Pulmonary Disease (COPD) is a progressive and heterogeneous condition characterized by varying combinations of emphysema, small airway disease, chronic bronchitis, and exacerbations. Although multiple symptomatic therapies exist, no disease-modifying treatments are available. This gap highlights the need for improved preclinical models with greater translational relevance. Large human cohorts and single-cell/multi-mics studies have informed the development of current COPD models. We provide a state-of-the-art review of the major experimental platforms-in vivo (small and large animals, genetic and injury models, environmental exposures), ex vivo (precision-cut lung slices, organoids, co-cultures, lung-on-chip systems), and in silico (aerosol dispersion and computational tools). While each approach has yielded important mechanistic insights, none fully captures the complexity of COPD progression, comorbidities, gene-environment interactions, or heterogeneous clinical endotypes. Future progress will depend on the development of more integrated, human-relevant modeling systems, alongside advanced exposure platforms and AI-driven multi-omics integration to identify biologically meaningful endotypes and speed the creation of phenotype-specific therapies. We propose a phenotype-driven, cross-platform framework in which hypotheses emerging from human clinical and omics data, are validated in in vitro and ex vivo systems, evaluated in phenotype-specific in vivo models, and ultimately confirmed through clinical studies.
- Polverino, F.
- Benam, K. H.
- Cloonan, S. M.
- Curtis, J. L.
- Gaggar, A.
- Kheradmand, F.
- Lehmann, M.
- Neptune, E.
- Raju, S. V.
- Rojas-Quintero, J.
- Sauler, M.
- Tesfaigzi, Y.
- Yildirim, A. O.
- Zhou, A. X.
- Sin, D. D.
