and Jürgen Roth2
Medical University of Vienna, Vienna, Austria
University of Zurich, Zurich, Switzerland
The Tracheo-Bronchial Epithelium
The upper part of the respiratory tract functions as an air-conducting system. Here, warming and moistening of the inhaled air and removal of inhaled particles occurs. It is lined by the pseudostratified respiratory epithelium, which consists of four cell types: (1) columnar ciliated cells, which possess cilia that project from their apical plasma membrane and function in the autonomous, coordinated movement of luminal content; (2) goblet cells (MC in A), unicellular glands synthesizing and secreting mucus, forming part of the mucus blanket, which functions as a lubricant and a protective layer; (3) a small number of neuroendocrine cells (also referred to as Kultschinsky cells), dispersed in the epithelium; and (4) basal cells, which function as stem cells for the regeneration of the respiratory epithelium.
The cilia, 4–6 μm in length, are motile cytoplasmic extensions of the ciliated cells (panel A). Their core structure is the axoneme (AX in panel B), a microtubule-based structure, surrounded by the plasma membrane (panels B–D, and diagram). The axoneme is composed of one central microtubule pair and nine peripheral arranged microtubule doublets, the so-called 9 + 2 arrangement (panel C, and C in diagram). As shown in panel C and the diagram, the peripheral microtubule doublets consist of one complete microtubule (A-microtubule composed of 13 protofilaments), which is attached to an incomplete microtubule (B-microtubule composed of 10 protofilaments). Toward the tips of the cilia, the axoneme consist of 9 single peripheral microtubules and a central pair (panel D).
The 9 + 2 arrangement is joined and stabilized by accessory proteins. Radial spokes (S in diagram) extend from the A-microtubules and insert toward the inner sheet, which surrounds the central microtubule pair. They participate in the conversion of the microtubule sliding into a bending movement. The peripheral microtubule pairs are connected to each other by nexin filaments (N in diagram), which are important for the maintenance of the axoneme structure during microtubule sliding. From the A-microtubules, pairs of dynein arms (O and I in the diagram) extend. Dyneins, which are microtubule-associated ATPases, are instrumental in microtubule sliding. Upon ATP hydrolysis by dyneins, the outer doublets slide relative to each other, resulting in bending of the cilia. Thus, sliding and bending is the basis for ciliary movement. Cilia move with a rapid effective forward stroke and a slow, whip-like recovery stroke. All cilia beat in the same direction, slightly out of phase, and transport the mucus layer with entrapped particles toward the pharynx. In the absence of the outer dynein arms, slow ciliar beating is still possible. In addition to this function in mechanical defense, motile cilia have bitter taste receptors.
Axonemata are anchored to basal bodies (BB in panel B), which consist of nine microtubule triplets (panel E). Basal bodies are modified centrioles and act as growth templates for the outer microtubule pairs. At the distal ends of basal bodies, so-called roots can be recognized (R in panel B). Between the cilia, short, often branched, microvilli-like extensions of the plasma membrane can be observed (panel A, MV in panel B).
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Magnification: 6,000 (A); ×25,000 (B); ×60,500 (C); ×68,000 (D); ×94,000 (E)
Ciliopathies: Immotile Cilia Syndrome and Kartagener Syndrome
Functional impairment or lack of the ciliary machinery of the respiratory epithelium, the ciliopathies, results in serious chronic airway disease. Owing to lacking, deficient, or uncoordinated ciliar motility, muco-ciliary clearance is affected. This results in accumulation of mucus and particles, including bacteria and viruses. This condition is known as the immotile cilia syndrome or ciliary dyskinesia and includes the Kartagener syndrome.
The immotile cilia syndrome is a heterogeneous disease, and several different ultrastructural alterations of the cilia have been documented. However, the relation between functional impairment and altered ultrastructure of cilia is not always clear. In extreme cases, only isolated cilia (arrow in panel A) or no cilia at all may be found, as illustrated in panel B. Only microvilli-like structures exist (MV in panels A and B). Sometimes, remnants of basal body-like structures can be observed (arrowheads in panel A). More commonly observed are the following defects of cilia: (a) absence or reduction in number of outer and inner dynein arms; (b) outer or inner dynein arm deficiency; (c) shortening of outer dynein arms and absence of inner dynein arms (panel C); (d) spoke defects such as complete absence or missing spoke heads; (e) peripheral microtubule abnormalities with single microtubules (panel D); (f) missing pair of central microtubuli with transposition of a peripheral one (upper axoneme in panel E); (g) supernumerary pair of central microtubuli (upper axoneme in panel F); and (h) or single central microtubulus (upper axoneme in panel G). It should be noted that cilia with normal ultrastructure may be immotile or dysmotile.