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

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.

The Effect of Sodium Bicarbonate, a Beneficial Adjuvant Molecule in Cystic Fibrosis, on Bronchial Epithelial Cells Expressing a Wild-Type or Mutant CFTR Channel

“…We have successfully established and characterized a new, physiologically more relevant co-culture model of cystic fibrosis using the CFBE cell line. This cell line, derived from samples from a CF patient, is widely used for studies on disease pathology and to test possible pharmacological treatments [25,26]. To better understand CF pathology, CFBE cells, which do not express endogenous CFTR, were transfected with WT and ∆F508-CFTR channels by several groups [14,17,20].…”

Animal Models Reflecting Chronic Obstructive Pulmonary Disease and Related Respiratory Disorders: Translating Pre-Clinical Data into Clinical Relevance

“…Primary cells obtained directly from patients through lung resections, bronchoalveolar lavage fluid extraction, and biopsies offer a more patient-specific phenotype compared to immortalized cell lines [142,143]. The utility of these cell lines is increased when used as structurally representative models such as air-liquid interface (ALI) cultures, which facilitate cell differentiation and the development of structural features such as cilia [144][145][146]. A noteworthy drawback of using in vitro cultured cells is their removal from the extracellular matrix and milieu of inflammatory cells, potentially skewing readouts and resulting in poor translational value for clinical application [143].…”

Deciphering the Ecology of Cystic Fibrosis Bacterial Communities: Towards Systems-Level Integration

“…Nevertheless, to properly address predictive mathematical models of CF-microbiome interactions, both large studies (cross-sectional and longitudinal) and proper in vitro and in vivo animal models are needed (Box 1). Indeed, while in vitro models have been used to investigate pathogen physiology and identify molecular-level interactions between cells [96][97][98][99][100], animal models allow for more in depth and nuanced investigation of ecological dynamics of CF microbiota and could provide relevant opportunities to experimentally validate predictions [101][102][103]. These could allow researchers to investigate functional interactions among members of the microbiome in vivo and in simplified simulated conditions (e.g., lung organoids) as well as the role of specific taxa in microbiome dynamics in health and in response to perturbation [104].…”

“…Animal models (e.g., mouse, ferret, pig, sheep) provide opportunities to experimentally manipulate the microbiome in the host and validate predictions [99][100][101].…”