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.