Particle Deposition onto the Mucociliary System Depends on Particle Size and Occurs by Impaction, Sedimentation, and Diffusion

Harmful material is inhaled as aerosols suspended in air or as toxic gases. The term aerosol refers to collections of particles or liquid droplets that are small enough to remain suspended in air for a period of time. For epidemiological purposes, particles are generally described as inhalable or respirable. Inhalable particulates have a mass median diameter of 10 microns (micrometers, µm) or less (referred to as PM10). Respirable particulates have a diameter of 2.5 µm or less (PM2.5). Ample evidence now indicates that increases in the atmospheric concentrations of PM10 or PM2.5 are associated with worsening of respiratory disease and increased hospital admissions for cardiopulmonary disease in people. Intensively housed animals can be exposed to PM10 and PM2.5 concentrations as great as those known to cause respiratory disease in humans.

Particles and aerosols are removed from the air when they contact the moist epithelial surface of the tracheobronchial tree (Figure 50-1). The distance that particles and aerosols travel into the tracheobronchial tree depends on particle size. Larger particles, greater than 5 µm in diameter, contact the airway wall by inertial impaction. Inertial impaction occurs at the bends in the large airways because large particles traveling at high velocity have so much momentum that they fail to negotiate the turns. At sites of inertial impaction there are accumulations of lymphoid tissue, such as tonsils and bronchus-associated lymphoid tissue, presumably to orchestrate an immune response to the material landing on the airway surface. As airflow rates diminish deeper in the lung, particles 1 to 5 µm in diameter settle onto the walls of the airways by sedimentation. The smallest particles reach the peripheral airways and alveoli, where they either contact the epithelial surface by diffusion or are exhaled again. Inhaled drugs must be delivered in a form with a particle size of 1 to 5 µm to be deposited onto the airway wall and remain in the lungs.

The deposition of particles within the respiratory tract is influenced by the pattern of breathing. Slow, deep breathing transports particles deep into the lung, whereas rapid, shallow breathing enhances inertial deposition in the larger airways. Bronchoconstriction enhances deposition of particles in more central airways, whereas bronchodilation favors more peripheral distribution.

The deposition of toxic gases depends on their solubility and concentration. Highly soluble gases, such as sulfur dioxide (SO₂), in low concentrations are removed by the nose, but in higher concentrations they can penetrate deeper into the lung. Less soluble gases can gain access to the alveoli. Toxic gases stimulate a variety of protective mechanisms, such as bronchospasm, mucus hypersecretion, coughing, and sneezing.

The Respiratory Tract Is Lined by a Mucociliary Blanket Consisting of a Ciliated Epithelium Overlaid with a Layer of Mucus

Particles deposited on the epithelial surface of the respiratory tract are transported on the mucociliary escalator to the pharynx, where they are then swallowed. The mucociliary system consists of sol and gel mucus layers overlying epithelial cells (Figure 50-2). The low-viscosity sol layer, in which the cilia beat, bathes the surface of the epithelial cells. On its forward stroke, the extended cilium catches the overlying viscous gel layer, in which inhaled particles are entrapped, and propels it up the tracheobronchial system or through the nasal cavity. Because the total surface area of the peripheral airways is so much greater than that of the trachea, differential rates of mucus transport are necessary in small and larger airways to prevent the accumulation of mucus in the trachea. Clearance rates and the beating frequency of cilia are slower in bronchioles than in bronchi and trachea. In large mammals, gravity also plays an important role in speeding mucociliary clearance. If a horse is prevented from lowering its head, the rate of mucociliary clearance is reduced. As a consequence, the number of bacteria in the trachea increases and this can lead to pneumonia. Inability of horses to lower their heads in a horse trailer may explain why transportation over long distances is the greatest risk factor for development of pneumonia in horses.

Respiratory tract mucus originates from several sites (see Figure 50-2). In respiratory bronchioles the conciliated Clara cells are a source of the fluid that lines the airways. In the larger airways, goblet cells produce mucous secretions. In the bronchi, submucosal bronchial glands produce both serous and mucous secretions. Secretion is under autonomic regulation. Throughout the respiratory tract, transepithelial movement of water and ions can change the composition of the mucus layer. Ion and fluid exchange is assisted by microvilli on the surface of epithelial cells.

Changes in the amount, composition, and viscosity of mucus occur in response to many stimuli and can be the cause or the result of respiratory disease. Normal airway epithelia regulate the rates of Na⁺ absorption and Cl^– secretion to regulate the depth of the mucous layer for optimal ciliary function. A change in the depth or viscosity of the sol layer impairs ciliary function, and changes in the viscoelastic properties of the gel layer alter clearance rates. Increased viscoelasticity and decreased clearance can be caused by an increased amount of deoxyribonucleic acid (DNA) in mucus. Decreased clearance occurs during bacterial infections of the lung when both bacterial DNA and neutrophil DNA are present in mucus.

Coughing is part of the clearance mechanism of the respiratory tract and is initiated by stimulation of subepithelial irritant receptors, which are most numerous in the larger bronchi. Receptors can be stimulated by the mechanical deformation that results from foreign bodies or excessive amounts of material such as mucus on the epithelial surface. The cough reflex becomes hyperresponsive when the air passages are inflamed and respiratory tract epithelium is injured (e.g., by viral infections). Cough is effective in clearing mucoid secretions from the intrathoracic trachea and large bronchi, but it does not assist in removing mucus from the more peripheral bronchi and bronchioles.

Alveolar Macrophages Scavenge Particles Deposited on the Alveolar Surface

Macrophages, which constitute the majority of cells in the alveolar lining fluids, are the principal resident phagocytes in the normal lung. Macrophages originate in bone marrow as monocytes and differentiate during their passage from the blood into the alveolus, where their turnover time is in days. Surfactant proteins, complement, opsonins, and lysozymes in respiratory tract secretions assist macrophages in the killing and removal of viable particulates, such as bacteria. When phagocytized, particles are destroyed or transported out of the lung by the macrophage. Some macrophages enter the mucociliary system directly from the alveolus; others traverse the alveolar wall and enter the lymphoid tissues associated with the airways. In the lymphoid tissue, macrophages are antigen-presenting cells (APCs) and thus play a critical role in orchestrating the lung’s immune responses.

Macrophages have adapted to the high oxygen levels of the alveolus, and their role as phagocytes is depressed by hypoxia. Macrophage function is also suppressed by endogenous glucocorticoids that are released from the adrenal glands at times of stress and by synthetic corticosteroids that are used to relieve inflammation (e.g., in arthritis). Stress-induced suppression of macrophage function contributes to respiratory disease in animals transported for long distances. In addition, excessive administration of synthetic corticosteroids can make animals more susceptible to bacterial infections of the lung. Viral infections also suppress macrophage function; this occurs approximately 7 days after virus inoculation (Figure 50-3) and contributes to the secondary bacterial infections that usually follow viral respiratory disease.