Abstract
Chronic inflammation, oxidative stress, mucus plugging, airway remodeling, and respiratory infections are the hallmarks of the cystic fibrosis (CF) lung disease. The airway epithelium is central in the innate immune responses to pathogens colonizing the airways, 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 human CF 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, and fibroblasts are instrumental in disease modeling, drug discovery, and identification of novel therapeutic targets. Nevertheless, they have to be implemented in the CF field yet. Finally, novel systems hijacking on tissue engineering, including three-dimensional cocultures, decellularized lungs, microfluidic devices, and lung organoids formed in bioreactors, will lead the generation of relevant human preclinical respiratory models a step forward.
Highlights
Cystic fibrosis (CF) is a recessive autosomal disease caused by mutations in the CFTR gene located on the long arm of chromosome 7
The primary scope of this review is to present and discuss the in vitro and ex vivo models of the airway epithelium obtained from human specimens; secondly, we will highlight the role of airway epithelial cells and their interplay with other immune cells in the generation of inflammation and mucus abnormalities in CF
Harrington et al [148] have used electrospun fibers of poly(ethylene terephthalate) (PET) to create a 3D model of the airway epithelium, comprising epithelial cells (Calu-3), dendritic cells (DCs), and fibroblasts, cultured at air-liquid interface (ALI) (Figure 2(d)), showing that cocultures recovered their integrity earlier than single cultures upon challenge with allergens and that they were amenable to DC migration from the bottom layer to the uppermost epithelial layer. 3D coculture models of airway epithelial cells (AECs), immune cells, and fibroblasts have not implemented in the CF field yet
Summary
Cystic fibrosis (CF) is a recessive autosomal disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene located on the long arm of chromosome 7. CF mice do not exhibit the severe pathology characteristic of established human CF lung disease consisting of chronic respiratory infection, inflammation, mucus plugging, and progressive bronchiectasis [18]. The lack of these features can be traced back to different reasons, among which are alternative chloride channels that supply the deficiency of CFTR and anatomical differences since human airways have numerous submucosal glands throughout the trachea and bronchi, while murine airways only have a small proportion of these glands in the larynx and proximal trachea [19]. We will emphasize similarities and differences between human-derived cell models and animal findings in relation with inflammation as well as mucus production and lung disease
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