Muscarinic receptor antagonists and airway inflammation: A systematic review on pharmacological models

: Airway inflammation is crucial in the pathogenesis of many respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. Current evidence supports the beneficial impact of muscarinic receptor antagonists against airway inflammation from bench-to-bedside. Considering the numerous sampling approaches and the ethical implications required to study inflammation in vivo in patients, the use of pre-clinical models is inevitable. Starting from our recently published systematic review concerning the impact of muscarinic antagonists, we have systematically assessed the current pharmacological models of airway inflammation and provided an overview on the advances in in vitro and ex vivo approaches. The purpose of in vitro models is to recapitulate selected pathophysiological parameters or processes that are crucial to the development of new drugs within a controlled environment. Nevertheless, immortalized cell lines or primary airway cells present major limitations, including the inability to fully replicate the conditions of the corresponding cell types within a whole organism. Induced animal models are extensively used in research in the attempt to replicate a respiratory condition reflective of a human pathological state, although considering animal models with spontaneously occurring respiratory diseases may be more appropriate since most of the clinical features are accompanied by lung pathology resembling that of the human condition. In recent years, three-dimensional organoids have become an alternative to animal experiments, also because animal models are unable to fully mimic the complexity of human pulmonary diseases. Ex vivo studies performed on human isolated airways have a superior translational value compared to in vitro and animal models, as they retain the morphology and the microenvironment of the lung in vivo. In the foreseeable future, greater effort should be undertaken to rely on more physiologically relevant models, that provide translational value into clinic and have a direct impact on patient outcomes.