Within the airway lining fluid there are two distinct layers,^4,5 a periciliary or ‘sol’ layer which is of low viscosity containing water and solutes and in which the cilia are embedded, and a mucous or ‘gel’ layer above.

Mucous layer. Large airways are completely lined by a mucous layer, whilst in smaller, more distal, airways the mucous is found in ‘islands’, and a mucous layer is absent in small bronchioles and beyond. Mucous is composed mostly of glycoproteins called mucins,^6,7 which determine the visco-elastic and other properties of the mucous. Mucin is released by rapid (<150 ms) exocytosis from the mucous secreting goblet cells in response to a range of stimuli including direct chemical irritation, inflammatory cytokines⁸ and neuronal stimulation, predominantly by cholinergic nerves.^9,10 Mucins have a core composed of glycoprotein subunits joined by disulphide bonds and their length may extend up to 6 μm. The core is 80% glycosylated with side chains attached via O-glycosidic bonds. Almost all terminate in sialic acid and possess micro-organism binding sites. Mucous plays a vital role in pathogen entrapment and removal, and also has a variety of antimicrobial actions (see below).

Ciliary function.^11,12 The mucous layer is propelled cephalad by the ciliated epithelial cells (Figure 12.1) at an average rate of 4 mm.min⁻¹, to be removed by expectoration or swallowing on reaching the larynx and pharynx. The cilia beat mostly within the low-viscosity periciliary layer of airway lining fluid, with the cilia tips intermittently gripping the underside of the mucous layer, so propelling the mucous layer along the airway wall.

Fig. 12.1 Scanning electron micrograph of ciliated epithelial cells beneath the mucous (Mu) lining the larger airways.

(Kindly reproduced by permission of Dr P. K. Jeffery, Imperial College School of Science, Technology and Medicine, London and the publishers of Respiratory Medicine.¹³)

Cilial beat frequency is 12–14 beats per second and can be affected by pollutants, smoke, anaesthetic agents and infection. Two phases occur for each beat (Figure 12.2). First is the recovery stroke which occupies 75% of the time of each cycle and involves a slow bowing movement away from the resting position by a sideways action of the cilium. There then follows the effective stroke in which the cilium extends to its full height, gripping the mucous layer above with claws on its tip, before moving forward in a plane perpendicular to the cell below and returning to its resting position. Adjacent cilia somehow coordinate their strokes to produce waves of activity that move the mucous layer along, probably by a physical effect of cilia stimulating adjacent cilia during the sideways sweep of the recovery stroke.

Fig. 12.2 Mechanism of action of a single cilium on the respiratory epithelium. (A) Recovery stroke in which the cilium bows backwards and sideways within the low-viscosity periciliary layer. (B) Effective stroke in which the cilium extends perpendicular to the epithelial cell into the mucous layer and propels it forwards. The blue line shows the trajectory of the cilium tip.

Periciliary layer. For this propulsion system to work effectively, it is crucial that the depth of the periciliary fluid layer be closely controlled,^4,5 particularly considering the increasing amount of mucus that will occur each time two smaller airways converge into one larger airway. The depth of both layers of the airway lining fluid is controlled by changes in the volume of secretions and the speed of their re-absorption. If the periciliary layer reduces in depth, the gel layer will compensate for this by donating liquid to the periciliary layer to maintain the correct depth of fluid, an effect probably mediated by simple osmotic gradients between the two layers. The mucous layer may donate fluid to the periciliary layer until its volume is diminished by 70%. The reverse happens as the mucus converges on the larger airways, with the mucous layer absorbing excess periciliary water. The volume of periciliary fluid is therefore effectively determined by its salt concentration, which is in turn controlled by active ion transport on the surface of the epithelial cells. The ion channels responsible for active control are amiloride sensitive Na⁺ and Cl⁻ channels, the latter better known as the cystic fibrosis transmembrane regulator (CFTR) protein. CFTR is likely to be partially active at rest but is stimulated when Na⁺ channels are inhibited. The factors responsible for this critical system are unknown, though adenosine diphosphate release in response to cyclical airway movements may be involved.¹⁴

In patients with cystic fibrosis an inherited defect of CFTR leads to dysfunction in the regulation of airway lining fluid homeostasis, with severe consequences (Chapter 28).

Humidification. The airway lining fluid acts as a heat and moisture exchanger to humidify and warm inspired gas. During inspiration, relatively cool, dry air causes evaporation of surface water and cooling of the airway lining, then on expiration moisture condenses on the surface of the mucous and warming occurs. Thus only about one half of the heat and moisture needed to condition (fully warm and saturate) each breath is lost to the atmosphere. With quiet nasal breathing, air is conditioned before reaching the trachea, but as ventilation increases smaller airways are recruited until at minute volumes of over 50 l.min⁻¹ airways of 1 mm diameter are involved in humidification.

Where in the respiratory tract inhaled particles are deposited depends on both their size and the breathing pattern during inhalation. Three mechanisms cause deposition:

Aiding all these mechanisms is the high humidity within the respiratory tract. Absorption of water by the particle during its journey along the airways will increase the particle’s weight, and so encourage both inertial impaction and sedimentation to occur. Naturally this affects hygroscopic particles to a greater degree.

As an interface with the outside environment the lung is exposed to a great many organisms carried by the ∼20 000 litres of air breathed each day. Pulmonary defence mechanisms have evolved to protect the respiratory tract from invasion by micro-organisms. They can be subdivided into direct removal of the pathogen, chemical inactivation of the invading organism and, if these fail, immune defences.

Direct removal of pathogens. With normal nasal breathing, a majority of inhaled pathogens impact on the nasal mucosa, which is swept backwards by the ciliated nasal epithelium and swallowed. At higher inspiratory flow rates, for example when dyspnoeic, pathogens will penetrate deeper into the airways and be trapped by the sticky mucous layer of the airway lining fluid, before being removed.

Chemical inactivation of pathogens.¹⁵ Airway lining fluid is more than a simple transport mechanism for impacted micro-organisms. Some smaller particles will penetrate far into the bronchial tree and take some time to be transported out of the respiratory tract. To prevent these organisms from causing damage during this time, the airway lining fluid contains multiple systems for directly killing pathogens. Surfactant, in addition to its role in reducing lung compliance (page 30), also acts as part of the innate defences in the lung.¹⁶ Surfactant protein A is the most active surfactant protein in pulmonary defence, its actions including stimulating macrophage migration, the production of reactive oxygen species, and the synthesis of immunoglobulins and cytokines. Both surfactant protein A and D are directly bactericidal,¹⁷ with activity against many common pulmonary pathogens. Lysozyme is also present in airway lining fluid. This enzyme, secreted by neutrophils, is capable of destroying microbial cell walls causing bacterial lysis, particularly for Gram-positive bacteria.

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