Human Cellular Models for the Investigation of LungInflammation and Mucus Production in Cystic Fibrosis

Chronic inflammation, oxidative stress, mucus plugging, airway remodeling, and respiratory infections are the hallmarks of thecysticfibrosis (CF) lung disease. The airway epithelium is central in the innate immune responses to pathogens colonizing theairways, since it is involved in mucociliary clearance, senses the presence of pathogens, elicits an inflammatory response,orchestrates adaptive immunity, and activates mesenchymal cells. In this review, we focus on cellular models of the humanCF airway epithelium that have been used for studying mucus production, inflammatory response, and airway remodeling,with particular reference to two- and three-dimensional cultures that better recapitulate the native airway epithelium.Cocultures of airway epithelial cells, macrophages, dendritic cells, andfibroblasts are instrumental in disease modeling, drugdiscovery, and identification of novel therapeutic targets. Nevertheless, they have to be implemented in the CFfield yet.Finally, novel systems hijacking on tissue engineering, including three-dimensional cocultures, decellularized lungs, microfluidicdevices, and lung organoids formed in bioreactors, will lead the generation of relevant human preclinical respiratory models astep forward.