Efficient mucociliary transport relies on efficient regulation of ciliary beating

https://doi.org/10.1016/j.resp.2008.05.010Get rights and content

Abstract

The respiratory mucociliary epithelium is a synchronized and highly effective waste-disposal system. It uses mucus as a vehicle, driven by beating cilia, to transport unwanted particles, trapped in the mucus, away from the respiratory system. The ciliary machinery can function in at least two different modes: a low rate of beating that requires only ATP, and a high rate of beating regulated by second messengers. The mucus propelling velocity is linearly dependent on ciliary beat frequency (CBF). The linear dependence implies that a substantial increase in transport efficiency requires an equally substantial rise in CBF. The ability to enhance beating in response to various physiological cues is a hallmark of mucociliary cells. An intricate signaling network controls ciliary activity, which relies on interplay between calcium and cyclic nucleotide pathways.

Introduction

Cilia are cellular protrusions covered by cellular membrane, which exist in a wide range of organisms and tissues from protozoa to the digestive, reproductive and respiratory system of vertebrates. Their main function is propulsion of water or mucus. Mucus-bearing ciliary systems are composed of three layers: an epithelial layer of ciliary cells; periciliary liquid of low viscosity, which surrounds the cilia; and the upper mucus layer, which is propelled by the cilia. The respiratory mucociliary epithelium is a synchronized and highly effective waste-disposal system. It uses mucus as a vehicle, driven by beating cilia, to transport unwanted particles, trapped in the mucus, away from the respiratory system. The ability of cilia, tiny hairlike protrusions (diameter 0.25 μm, length 5–7 μm and packing density 100–200 per cell), to propel steel beads of 1 mm in diameter at a speed of 0.5 mm/s is amazing (King et al., 1974). This titanic task is achieved due to the high degree of coordination between the individual cilia, and due to the ability of cilia to respond, quickly and for prolonged periods of time, to various stimuli by increasing drastically the ciliary beat frequency (CBF).

The ciliary machinery can function in at least two different modes: a low rate of beating that requires only ATP and most probably involves only the ciliary motor, and a high rate of beating that involves, in addition, a controlling device regulated by second messengers (Ma et al., 2002). To enable response to varying environmental conditions, ciliary cells possess a relatively large variety of different receptors capable of inducing intracellular events that lead to CBF enhancement, including purinergic, adrenergic and cholinergic receptors (Verdugo et al., 1980, Ovadyahu et al., 1988, Sanderson and Dirksen, 1989, Villalon et al., 1989, Mason et al., 1991, Weiss et al., 1992, Wong and Yeates, 1992, Gheber et al., 1995, Salathe et al., 1997, Zagoory et al., 2001, Salathe, 2007).

The periodic beating of cilia is achieved by the function of its complex internal apparatus (Satir and Christensen, 2007). Its core, the axoneme, consists of nine microtubule pairs (doublets) encircling the central pair. Adjacent doublets are linked by nexin filaments, whereas the central pair is connected to the surrounding microtubules by radial spokes. These links provide both structural stability and elasticity, allowing repetitive bending of the axoneme. The beating is powered by the activity of the microtubule-based dynein motor protein, which is attached to the outer microtubule doublets and utilizes ATP hydrolysis to produce active sliding of adjacent microtubule doublets (Summers and Gibbons, 1971). There are both inner and outer dynein arms on each doublet, and they occur in equal spacing along all of the doublet's lengths (Avolio et al., 1986).

This review will attempt to summarize the current state of knowledge regarding the mechanistic aspects of ciliary beating as well as the intricate intracellular signaling machinery regulating ciliary activity.

Section snippets

Physical properties of mucociliary transport

The beat pattern of mucus-propelling cilia is asymmetric. It consists of two main parts or strokes, the fast effective stroke and the slower recovery stroke (Fig. 1). During the effective stroke, the cilia are nearly in an upright position, moving in a plane perpendicular to the cell surface (Sanderson and Sleigh, 1981). This enables ciliary tips to embed in the mucus and propel it. During the recovery stroke, the cilia are bent, moving in an incline to the cell surface plane and avoiding

Regulation of ciliary beating by calcium

Many cellular events are triggered by changes in the cytoplasmic concentration of calcium ions (Berridge et al., 2000, Berridge et al., 2003, Petersen et al., 2005, Case et al., 2007). Calcium ions bind to many different cellular proteins, modifying their activity and consequently affecting the behavior of the entire cell. It is well established that Ca2+ is an important regulator of ciliary beating. In water-propelling cilia, calcium influx through voltage-gated calcium channels is responsible

Integration of signaling pathways regulating ciliary beating

In addition to Ca2+, cAMP and/or cGMP are important modulators of ciliary activity in a variety of ciliary systems (Tamaoki et al., 1989, Lansley et al., 1992, Geary et al., 1995, Yang et al., 1996, Braiman et al., 1998, Braiman et al., 2001b, Uzlaner and Priel, 1999, Zagoory et al., 2002, Zhang and Sanderson, 2003, Wyatt et al., 2005, Schmid et al., 2006, Salathe, 2007). The cAMP-dependent protein kinase (PKA) has been shown to phosphorylate specific axonemal targets that increase the forward

Summary

The respiratory mucociliary epithelium is a highly effective waste-disposal system. This task is achieved due to the high degree of coordination between the individual cilia, and due to the ability of cilia to increase drastically the ciliary beat frequency in response to various stimuli. On an active ciliary area there is a phase difference between beating cilia, creating a wave often referred to as the “metachronal wave” or “metachronism”, which allows for a large number of individual cilia

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