Mucociliary clearance: History
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Subjects: Cell Biology
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Suneel Kateriya

Mucociliary clearance constitutes an innate lung defense mechanism that is primarily driven by ciliated cells. Respiratory mucus traps pathogens entering the airways, and lung cilia propel them outward via their coordinated directional motion. Thus, damage to the component(s) of this apparatus is averted and physiological function is ensured. 

  • Mucociliary clearance

1. Introduction

Life depends on the availability of oxygen in humans. The human respiratory system is an intricate interface for breathing and gaseous exchange. Coupled with the circulatory system, it ensures a constant oxygen supply to the living tissues and removes carbon di-oxide to properly sustain metabolic homeostasis. The air is filtered, warmed, and humidified during inhalation before traversing the trachea and the dichotomous respiratory airways. This air stream comes close, within one cell layer barrier, to the blood stream and thereby exposes the body, via the respiratory tract, to a myriad of foreign agents like pathogenic bacteria, viruses, gaseous, and particulate matter present in the inhaled air. However, the respiratory tract has sophisticated defenses to guard against these potentially noxious agents. Mucociliary clearance (MCC) is the innate lung defense machinery used to capture and clear inhaled foreign agents [1][2]. The airway mucosa is lined by a pseudostratified epithelium where the ciliated and secretory cells provide the primary barrier during abuse by a foreign agent [3][4]. The mucosa is covered by the airway surface layer (ASL). It includes a protective layer of mucus to ensnare the inhaled foreign elements and microbes, as well as a periciliary layer (PCL) for the lubrication of respiratory airways to facilitate efficient ciliary movement that drives effective mucus expulsion. In conjunction, the metachronal beating of cilia on the epithelial surface generates a wave-like motion that propels the pathogens including virus and particulates trapped within the mucus layer of the airways outward and towards the nose or mouth for their elimination via coughing or swallowing. Thus, in healthy individuals, an effective MCC system coordinates the mucus formation (that traps dust and pathogens to be propelled out) and the clearance of foreign agents mediated by cilia. Consequently, a weakened or defected functioning of this protection system  due to the malfunctioning of one or more components of the MCC apparatus manifest the development of chronic respiratory diseases that may be genetic or acquired, such as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF), and primary ciliary dyskinesia (PCD). Furthermore, smoking, air pollution, and the inhalation of dust or chemical particles (occupational hazards) also increase the risk for developing respiratory infections and airway diseases, thereby contributing to the global burden of pulmonary diseases [5][6]. Additionally, socio-ecological changes in the current century have resulted in the emergence of virulent pathogens, such as the coronaviruses, that target the respiratory tract. Among them, the infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has evolved into the pandemic coronavirus disease-19 (COVID-19). The current situation poses an enormous challenge for managing the pulmonary diseases with an unprecedented dimension. In this context, we review the important components of the human respiratory system with a specific focus on the MCC apparatus, highlighting the critical role of cilia and mucus to effectively clear pathogenic agents including COVID-19 entering the lungs. We also discuss the health hazards associated with a dysfunctional mucociliary clearance system. Finally, we present an insight into the impact of SARS-CoV-2 infection on molecules (proteins) associated with or involved in the mucociliary clearance system of the host.

2. Structure and Composition of the MCC Apparatus in Humans

For effective MCC function, the cilia on the surface of the ciliated epithelial cells interact with the ASL. It is composed of the PCL (~7 µm) coated with an overlying layer of mucus (~2–5 µm) (Figure 1c). It also includes a thin layer of surfactant that spreads mucus all over the epithelial surface. The PCL aids in the lubrication of airway surfaces that facilitate ciliary beating [7]. In totality, the ASL is critical for normal ciliary performance and to maintain healthy airways.

Mucus is a complex, gel-like secretion of a non-static nature. It is predominantly composed of the mucin glycoproteins that provide the structural framework to the mucus. It primarily functions within healthy airways to entrap foreign pathogens and particles, dissolve toxic gases, pollutants and assist in their removal from the lungs via an effective and directional ciliary beating and cough. Thus, the mucus layer possesses a movable function, and mucus with an aberrant rheological property is a key pathological feature of chronic airway diseases. In addition, mucus acts as a reservoir of host-protective proteins and polypeptides, helps in preventing ASL dehydration, and allows for pathogen sequestration by interaction with carbohydrate ligands. The respiratory mucus contains molecules such as secretory immunoglobulin A (IgA), defensins, and histatins for host defense [8][9].

The mucins produced by the goblet cells may be secretory or membrane-associated. These molecules exist in a condensed, dehydrated state within secretory granules until their discharge, either constitutively or by external factors such as inflammatory cytokines and growth factors, bacterial components, environmental, and chemical pollutants [10]. The hyper-secretion and accumulation of mucus is a key pathological feature of diseases like cystic fibrosis, COPD, and asthma that result from dysregulated mucin production stemming from goblet cell hyperplasia. In asthmatics, an acute airway response pathway that stimulates the over-production of mucins and bronchospasm prevails, thus resulting in airway obstruction that can be fatal [11].

Mucins are composed of a mucin domain that is rich in serine and threonine residues that are O-glycosylation sites. About 70% of the mass of the mucins is contributed by the carbohydrate groups that impart to it features of superior resistance to proteolysis and the sequestration of pathogens, along with an ion and water binding function [8]. A subset of secretory mucins also contains cysteine-rich amino and carboxy termini in addition to the glycosylated mucin domain. These mucins exist in the polymeric form via the formation of intra- and inter-molecular disulfide bonds. Any alteration of the organization of mucins within the mucus layer may result in pathological diseases where the layer’s transport properties and barrier function may be compromised.

Mucins are encoded by several MUC genes, of which MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC13, MUC15, MUC16, MUC17, MUC20, and MUC21 code for cell surface-associated mucins, and seven genes code for the secretory type (HUGO gene nomenclature committee, https://www.genenames.org/) [12]. Among the secretory mucins, MUC2, MUC5AC, MUC5B, MUC6, and MUC19 are oligomeric and gel-forming, while MUC7 and MUC8 are non-polymeric [8]. Normal mucus is a mixture of ~97% water, ~1% salt, ~1% mucins, and ~1% of other proteins [7][13]. It predominantly contains MUC5AC and MUC5B mucins with low levels of MUC2 [14][15][16].

The hydration of the ASL allows for efficient ciliary beating. ASL hydration occurs via an active transport of ions across the ciliated epithelium. Ciliated cells express the epithelial Na+ channel (ENaC) at their apical membrane, which allows for Na+ influx and the passive transport of H2O/Cl− across the ionic gradient and into the lumen. The regulation of the Cl− export occurs via the CFTR (cystic fibrosis transmembrane conductance regulator) and the CaCC (calcium-activated chloride channel) [17].

The PCL is a gel-like layer composed of the MUC1, MUC4, and MUC16 mucins and tethered mucopolysaccharides [18][19], which create an efficient lubrication layer for ciliary beating and also restrict the entry of foreign particulates. Its hydration status is also maintained via active transmembrane ionic transport [17]. The PCL volume is critical for effective MCC, as insufficient hydration causes the collapse of the mucus layer and the entrapment of cilia within the mucus, as seen in the case of cystic fibrosis [20].

This entry is adapted from the peer-reviewed paper 10.3390/biology10020095

References

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  8. Thornton, D.J.; Rousseau, K.; McGuckin, M.A. Structure and function of the polymeric mucins in airways mucus. Annu. Rev. Physiol. 2008, 70, 459–486.
  9. Rogan, M.P.; Geraghty, P.; Greene, C.; O’Neill, S.; Taggart, C.C.; McElvaney, N.G. Antimicrobial proteins and polypeptides in pulmonary innate defence. Respir. Res. 2006, 7, 29.
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  11. Rogers, D.F. Airway mucus hypersecretion in asthma: An undervalued pathology? Curr. Opin. Pharmacol. 2004, 4, 241–250.
  12. Braschi, B.; Denny, P.; Gray, K.A.; Jones, T.E.M.; Seal, R.L.; Tweedie, S.; Yates, B.; Bruford, E.A. Genenames.org: The HGNC and VGNC resources in 2019. Nucleic Acids Res. 2019, 47, D786–D792.
  13. Hamed, R.; Fiegel, J. Synthetic tracheal mucus with native rheological and surface tension properties. J. Biomed. Mater. Res. Part. A 2014, 102, 1788–1798.
  14. Kirkham, S.; Sheehan, J.K.; Knight, D.; Richardson, P.S.; Thornton, D.J. Heterogeneity of airways mucus: Variations in the amounts and glycoforms of the major oligomeric mucins MUC5AC and MUC5B. Biochem. J. 2002, 361, 537–546.
  15. Davies, J.R.; Svitacheva, N.; Lannefors, L.; Kornfalt, R.; Carlstedt, I. Identification of MUC5B, MUC5AC and small amounts of MUC2 mucins in cystic fibrosis airway secretions. Biochem. J. 1999, 344, 321–330.
  16. Hovenberg, H.W.; Davies, J.R.; Herrmann, A.; Linden, C.J.; Carlstedt, I. MUC5AC, but not MUC2, is a prominent mucin in respiratory secretions. Glycoconj. J. 1996, 13, 839–847.
  17. Tarran, R.; Button, B.; Picher, M.; Paradiso, A.M.; Ribeiro, C.M.; Lazarowski, E.R.; Zhang, L.; Collins, P.L.; Pickles, R.J.; Fredberg, J.J.; et al. Normal and cystic fibrosis airway surface liquid homeostasis. The effects of phasic shear stress and viral infections. J. Biol. Chem. 2005, 280, 35751–35759.
  18. Button, B.; Cai, L.-H.; Ehre, C.; Kesimer, M.; Hill, D.B.; Sheehan, J.K.; Boucher, R.C.; Rubinstein, M. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science 2012, 337, 937–941.
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  20. Sleigh, M.A.; Blake, J.R.; Liron, N. The propulsion of mucus by cilia. Am. Rev. Respir. Dis. 1988, 137, 726–741.
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