Mucociliary clearance

Cilia are thin cylindrical hair-like structures with a cross-sectional radius of 0.1 gm projecting from the apical epithelial surface of ciliated columnar cells. Ciliary length is thought to correspond to periciliary fluid depth and range from approximately 7 gm in proximal airways to roughly 5 gm in more distal airways.- Each ciliated epithelial cell supports approximately 200 cilia at a density of eight cilia/gm. Short microvilli, possibly associated with secretory functions, are interspersed among the cilia. 

Nonciliated cells separate fields of ciliated epithelial cells from each other. Synchronized ciliary movement, with a beat frequency in human proximal airways under normal conditions of 8-15 EIz, propels mucus along the mucociliary escalator at a rate of up to 25 mm/min. Beat frequencies appear to slow to roughly 7 Hz in more distal airways. Cilia move in the same direction and in phase within each field but cilia in adjacent fields move in slightly different directions and are phase shifted. These beat patterns result in metachronal waves that steadily move mucus at higher velocities ( -12-18 mm/min) than would be achievable by summing the motion of individual cilia. 

Mucus gel is propelled toward the epiglottis by a two-phase ciliary beat cycle. Forward mucus movement occurs during the effective or power phase of the cycle, when cilia fully extend and traverse an arc perpendicular to the epithelial surface (Fig. 5.24). Claw-like structures, 25-35 nm long, project from each cilia tip and appear to assist in the mechanical transfer of momentum from cilia to mucus gel. Maximum mucus velocity depends on the extent cilia penetrate the epiphase during the power phase, periciliary and mucus gel viscosity, and cilia density. 

During the recovery or preparatory phase, cilia bend over, swing back to start position generally parallel to the epithelial surface, and stiffen in anticipation of the next power phase. Ciliary bending and axial movement 

FIGURE 5.24 Components of ciliary movement, (a) Power and recovery phases of ciliary movement. Arrows indicate the direction of ciliary travel, (b) Net mucociliary transport. Dotted arrows show the direction of cilia while the solid arrows show mucus transport. Note that net gel movement is forward in I and III while no gel movement occurs in II during the cilia recovery phase. Modified from Ful-ford and Blake.  

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Disruption of these defense mechanisms can lead to bacterial colonization or viral infection. Mucus temperature is important in controlling respiratory infections because decreasing below central body core temperature not only impairs ciliary movement,hut also enhances viral replication,- greatly increasing the likelihood of respiratory infection. Drying of airway mucus also increases the possibility of respiratory infection by reducing mucus thickness and impairing mucociliary clearance, i- i--... 

The particle size is the most important factor that contributes to the clearance of particles. For particles deposited in the anterior parts of the nose, wiping and blowing are important mechanisms whereas particles on the other areas of the nose are removed with mucus. The cilia move the mucus toward the glottis where the mucus and the particles are swallowed. In the tracheobronchial area, the mucus covering the tracheobronchial tree is moved upward by the cilia beating under the mucus. This mucociliary escalator transports deposited particles and particle-filled macrophages to the pharynx, where they are also swallowed. Mucociliary clearance is rapid in healthy adults and is complete within one to two days for particles in the lower airways. Infection and inflammation due to irritation or allergic reaction can markedly impair this form of clearance. 

Airway clearance therapy is usually accompanied by bron-chodilator treatment [albuterol (also known as salbutamol outside the United States) by nebulizer or metered-dose inhaler] to stimulate mucociliary clearance and prevent bronchospasm associated with other inhaled agents. A mucolytic agent may be administered to reduce sputum viscosity and enhance clearance. 

Multiple factors play a role in the development of AOM. Viral infection of the nasopharynx impairs eustachian tube function and causes mucosal inflammation, impairing mucociliary clearance and promoting bacterial proliferation and infection. Children are predisposed to AOM because their eustachian tubes are shorter, more flaccid, and more horizontal than adults, which make them less functional for drainage and protection of the middle ear from bacterial entry. Clinical signs and symptoms of AOM are the result of host immune response and damage to cells caused by inflammatory mediators such as tumor necrosis factor and interleukins that are released from bacteria.4... 

Viscous middle ear effusions caused by allergy or irritant exposure may contribute to impaired mucociliary clearance and AOM in susceptible individuals.4 OME occurs chronically in atopic children, and effusion can persist for months after an episode of AOM. Children with chronic OME usually require tympanostomy tube placement to reduce complications such as hearing and speech impairment and recurrent otitis media. 

During absorption of this particular F-PHEA (Mw = 8.6 kD, Mn = 5.3 kD), through the rat lung, transfer occurred at an apparently constant rate of 110 43 ig/h or 3.5 1% of the administered dose per hour. Because mucociliary clearance from the lower airways occurs very slowly (7) these absorption rates convert to substantial bioavailabilities when the absorption process is extrapolated over a 12 h period [(3.5% x 12) or, around 42% may be feasible]. 

Selective sympathomimetics cause relaxation of bronchial smooth muscle and bronchodilation by stimulating the enzyme adenyl cyclase to increase the formation of cyclic adenosine monophosphate. They may also improve mucociliary clearance. 

Respiratory allergies and infections are the most common form of illness in the United States and Europe and account for more missed school and work days than any other disease [1], A substantial body of experimental work has clearly shown that airborne toxicants such as tobacco smoke, ozone, and other air pollutants can alter many aspects of the host defense network to either decrease resistance to infection, or exacerbate respiratory allergies and asthma [2], Exposure to air toxicants can suppress a number of key host defenses including mucociliary clearance in the airways, pulmonary macrophage function, and development of specific immune responses such as IgG antibody production and cell mediated immunity. In contrast, immune stimulation in the form of increased T cell activity and IgE antibody formation has also has been shown to occur under some circumstances, resulting in increased incidence or severity of allergic lung disease. 

Schlesinger, R.B., Naumann, B.D., and Chen, L.C., Physiological and histological alterations in the bronchial mucociliary clearance system of rabbits following intermittent oral or nasal inhalation of sulfuric acid mist, J. Toxicol. Environ. Health. 12, 2-3, 441, 1983. 

Mussatto, D.J., Garrad, C.S. and Lourenco, R.V (1988). The effect of inhaled histamine on human tracheal mucus velocity and bronchial mucociliary clearance. Am. Rev. Respir. Dis. 138 775-779. 

Pavia, D. (1984). Lung mucociliary clearance. In Aerosols and the Lung, Clinical and Experimental Aspects (Clarke, S.W. and Pavia, D., eds.). Butterworth, London, pp. 127— 155. 

Sackner, M.A. (1978). Effect of respiratory drugs on mucociliary clearance. Chest 73 (Suppl. 6) 958-966. 

The extent of drug absorption following nasal administration depends to a reasonable extent on the ease with which a drug molecule crosses the nasal epithelium without degradation or rapid clearance by the mucociliary clearance system. The effects of these two elimination components are more pronounced for proteins and peptides. The nasal administration of drugs, especially proteins and peptides, as well as other molecules has been studied with excised tissues harvested from rabbit, cow, sheep, and pig species (Table 5.2). A... 

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