Preclinical models of COPD: a state of the art review.

COPD is a progressive and heterogeneous condition characterised 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-omics 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-a-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 modelling systems, alongside advanced exposure platforms and artificial intelligence-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.