Mucociliary Defense: Emerging Cellular, Molecular, and Animal Models

Abstract

Respiratory tissues are bombarded by billions of particles daily. If allowed to accumulate, these particles can cause injury, inflammation, or infection, and thus may significantly disrupt airflow and gas exchange. Mucociliary defense, a primary mechanism for protecting host tissues, operates through the coordinated functions of mucus and cilia that trap and eliminate inhaled materials. Mucociliary function is also required for the elimination of endogenous cells and debris. Although defense is necessarily robust, it is also tightly regulated to minimize physiologic disruption of the host. Indeed, mucociliary dysfunction contributes to the pathogenesis of many lung diseases-including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and cystic fibrosis-in which airflow limitation, inflammation, persistent tissue injury, and structural remodeling occur. Here, we highlight recent advances in cilia and mucin biology, the importance of well-controlled mucociliary interactions, and the need to better understand how these regulate innate barrier and immune defense.

Chair’s Summary: Secreted Mucins in Lung Diseases

“…Christopher Evans reviewed the importance of mucociliary clearance for protection against inhaled particles and microbial pathogens (pp. S210-S215) (14). Richard Grencis described how MUC5AC upregulation in response to type 2 inflammation promotes the clearance of parasitic worms from the gut and their trapping within airways, as recently summarized elsewhere (15).…”

Preclinical Development of Orally Inhaled Drugs (OIDs)—Are Animal Models Predictive or Shall We Move Towards In Vitro Non-Animal Models?

“…As described in detail in Section 2.1.1, this feature is species-specific [59] and, therefore, human-specific removal mechanisms are not replicated by animal models. Notably, human-specific removal mechanisms can be reproduced by in vitro, cell-based NAMs [60][61][62][63], as discussed in detail in Section 2.2.…”

“…The clear advantage of lung-on-chip systems over ALI cultures or lung organoids is the possibility of mimicking the pulmonary mechanical stretch during in-and exhalation, while replicating the air-blood barrier for studying OID absorption. Furthermore, lung-on-chip models allow evaluating the impact of the mucociliary clearance mechanism overcoming the lack of directionality in cilia beating function characteristic of fully-differentiated in vitro ALI models [63]. Nevertheless, the lung-on-chip models share some of the limitations of ALI cultures, i.e., the impairment of physical crosstalk among different cell types.…”

Biological Obstacles for Identifying In Vitro-In Vivo Correlations of Orally Inhaled Formulations

“…Non-mammalian models (frog palate assay) can also be employed [61]. These conventional models lack directionality, but the more recently developed dynamic cultures, like the human small airway on a chip, overcome this limitation [100].…”