Cilia and Mucociliary Clearance

Abstract

Mucociliary clearance (MCC) is the primary innate defense mechanism of the lung. The functional components are the protective mucous layer, the airway surface liquid layer, and the cilia on the surface of ciliated cells. The cilia are specialized organelles that beat in metachronal waves to propel pathogens and inhaled particles trapped in the mucous layer out of the airways. In health this clearance mechanism is effective, but in patients with primary cilia dyskinesia (PCD) the cilia are abnormal, resulting in deficient MCC and chronic lung disease. This demonstrates the critical importance of the cilia for human health. In this review, we summarize the current knowledge of the components of the MCC apparatus, focusing on the role of cilia in MCC.

Figure 1.

Schematic representation of the airway epithelium. (A) The lower respiratory tract, functionally can be divided into conducting and respiratory zones. The adult human trachea has an internal diameter of ∼12 mm, cartilage plates, and smooth muscle. The trachea divides into right and left primary bronchi. A bronchus enters the lung at the hilum and then divides into bronchioles. After multiple bronchiolar branches (∼23 generations in humans), at the end of each respiratory bronchiole, the alveoli are found. (B) The trachea and most proximal airways are lined by a pseudostratified epithelium formed by ciliated and secretory cells. Basal cells are located in this region and they can generate secretory and ciliated cell lineages. (C) The small airways are lined by a simple cuboidal epithelium with fewer goblet cells, but are rich in club cells. (D) The alveoli are made of type I and type II alveolar cells.

Figure 2.

Representation of the components of the mucociliary clearance (MCC) apparatus. (A) An efficient MCC requires the cilia to interact with the periciliary layer (PCL) (∼7 mm) and propel the overlaying mucous layer (∼2 to 5 mm). A thin surfactant layer (in blue) could be present. The hydration of the airway surface layer (ASL) for optimal cilia performance is maintained by the active transmembrane ionic transport of the ciliated epithelia (dashed red box). (B) At the apical membrane, the Na⁺ reabsorption is mediated by epithelial Na⁺ channel (ENaC) with H₂O/Cl⁻ following passively the osmotic gradient. The Cl⁻ secretion is regulated by cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels (CaCC). The basolateral activity of the Na⁺/K⁺ ATPase, Na⁺/K⁺/2Cl⁻ cotransporter, voltage-dependent K⁺ channels, HCO3-/Cl⁻ exchanger, and other basolateral Cl⁻ channels, maintain the electrochemical gradient.

Figure 3.

Axonemal structure of the cilia. (A) The core structure of the cilia is the axoneme, as shown in the cross-sectional schematic diagram of a motile cilium displaying the characteristic 9+2 pattern, nine peripheral doublets microtubules surrounding a central pair of single microtubules. The cilia contain multiple protein complexes, including dynein arms, radial spokes, nexin–dynein regulatory complex (N-DRC), and inner sheath that connect the microtubules to each other. (B,C) Examples of single-cell immunofluorescence of human ciliated cells showing the localization of dynein heavy chain 5 (DNAH5) and radial spoke head 1 (RSPH1). Scale bars, 5 μm.

Figure 4.

Mutations found in PCD patients and their association to ultrastructural axonemal defects. Schematic representation of the axoneme in (A) cross-sectional, and (B) the longitudinal views of the 96 nm repeat. Mutations in >30 genes have been identified in patients with PCD. The affected gene and the corresponding axoneme defect are listed.