Multiscale mechanics of mucociliary clearance in the lung

Abstract

Mucociliary clearance (MCC) is one of the most important defence mechanisms of the human respiratory system. Its failure is implicated in many chronic and debilitating airway diseases. However, due to the complexity of lung organization, we currently lack full understanding on the relationship between these regional differences in anatomy and biology and MCC functioning. For example, it is unknown whether the regional variability of airway geometry, cell biology and ciliary mechanics play a functional role in MCC. It therefore remains unclear whether the regional preference seen in some airway diseases could originate from local MCC dysfunction. Though great insights have been gained into the genetic basis of cilia ultrastructural defects in airway ciliopathies, the scaling to regional MCC function and subsequent clinical phenotype remains unpredictable. Understanding the multiscale mechanics of MCC would help elucidate genotype-phenotype relationships and enable better diagnostic tools and treatment options. Here, we review the hierarchical and variable organization of ciliated airway epithelium in human lungs and discuss how this organization relates to MCC function. We then discuss the relevancy of these structure-function relationships to current topics in lung disease research. Finally, we examine how state-of-the-art computational approaches can help address existing open questions. This article is part of the Theo Murphy meeting issue 'Unity and diversity of cilia in locomotion and transport'.

Keywords: cilia biomechanics; genotype–phenotype relationships; lung disease; mucociliary clearance; multiscale mechanics; structure–function relationships.

Figure 1.

Elements and mechanics of MCC. (a) Brush-on-gel model of MCC: goblet cells produce gel-forming mucins that constitute the mucus layer as well as brush forming mucins in the PCL that tether to cell membranes. Multiciliated cells propel the mucus layer during the power stroke (black solid arrow) and move through the PCL during the recovery stroke (black dashed arrow) to achieve directional mucociliary clearance (orange solid arrow). (b) Important structure–function relationships of MCC at cellular and tissue level, including ciliary beat kinematics which depend on ciliary ultrastructure; metachronal beat facilitated by hydrodynamic coupling (HC) and, in interaction with the ASL rheology, leading to fluid flow; and rotational and tissue-level polarity of ciliary beat which is modulated by planar cell polarity (PCP) signalling, mechanical coupling (MC) of cytoskeletal elements and potentially the feedback from directional fluid flow forces. (Online version in colour.)

Figure 2.

Variability of lung epithelial composition in the tracheobronchial tree. The relative abundance of ciliated, secretory goblet and club cells, as well as basal cells changes as a function of airway branching level and diameter. Cell percentage values estimated from Crystal et al. [18] and Mercer et al. [19]. (Online version in colour.)

Figure 3.

Three research areas that involve the intimate relationship between MCC and local lung environment. (Online version in colour.)