Physical or Anatomic Factors

The pathway from the mouth or nose down to the lung parenchyma requires that inhaled air traverse a series of progressively branching airways. The laminar flow of air through the airways is disrupted at the branch points (subcarinae), thus enhancing deposition of particulate material at these locations. Hence, inhaled particulates frequently are deposited at various points in the airway, never reaching the most distal region of lung, the alveolar spaces. Particle size is an important determinant of deposition along the airway and thus affects the likelihood of a particle’s reaching the distal parenchyma. When an inhaled particle is greater than 10 µm in diameter, it is likely to settle high in the upper airway (e.g., in the nose). For particles 5 to 10 µm in diameter, settling tends to occur somewhat lower, in the trachea or the conducting airways, but not down to the level of the small airways and alveoli. The particles most likely to reach the distal lung parenchyma range in size from 0.5 to 5 µm. Many bacteria fall within this size range, so deposition along the airways is not very effective for excluding bacteria from the lower respiratory tract. However, large particles of dust and other inhaled material are effectively excluded from the distal lung parenchyma by virtue of their size. Of note, the target size for particles of inhaled medications such as bronchodilators is less than 5 µm so that the medication can bypass the conducting airways and reach the more distal lung.

When particles are deposited in the trachea or bronchi, two major processes, cough and mucociliary transport, are responsible for physical removal of these particles from the airways. Cough is an important protective mechanism, frequently triggered by stimulation of airway irritant receptors, which are most prominent in the proximal airways and are activated by inhaled or aspirated foreign material. Rapid acceleration and high flow rates of air achieved by a cough often are effective in clearing irritating foreign material from the airways.

The term mucociliary transport or mucociliary clearance refers to a process of waves of beating cilia moving a blanket of mucus (and any material trapped within the mucus) progressively upward along the tracheobronchial tree. From the trachea down to the respiratory bronchioles, the most superficial layer of epithelial cells lining the airway has cilia projecting into the airway lumen. These cilia have a structure identical to that of cilia found elsewhere in the body, consisting of longitudinal microtubules with a characteristic architecture. Specifically, a cross-sectional view of cilia shows two central microtubules surrounded by nine pairs of microtubules arranged around the periphery (Fig. 22-1). Small projecting side arms from each doublet, called dynein arms, are crucial to the contractile function of the microtubules and hence to the beating of the cilia.

Strikingly, the movement of cilia on a particular cell and the movement between cells are quite coordinated, producing actual “waves” of ciliary motion. Exactly how such a pattern of ciliary motion is coordinated from cell to cell or even within the same cell is not known. What this wavelike motion accomplishes is movement of the overlying mucous layer in a cephalad direction (i.e., from distal to more proximal parts of the tracheobronchial tree) at an estimated speed of 6 to 20 mm/min in the trachea. If inhaled particles are trapped in the mucous layer, they too are transported upward and eventually are either expectorated or swallowed.

Two layers comprise the mucous blanket bathing the epithelial cells. Directly adjacent to the cells is the sol layer, within which the cilia are located. The aqueous sol layer contains a number of molecules in solution that are part of the innate immune system and are discussed in the Antimicrobial Peptides section. Superficial to the sol layer is the more viscous gel layer, which is produced by both submucosal mucous glands and goblet cells. Picture the viscous gel layer floating on top of the sol layer and being propelled upward as the cilia are able to beat more freely within the less viscous sol layer.

Antimicrobial Peptides

The sol layer contains a number of substances that are important in innate immunity. The innate immune system can be thought of as a fast-acting system that is ready to quickly protect the lungs without prior sensitization and ideally avoid activation of the adaptive immune system (discussed in the Adaptive Immune Responses section). In addition to mucociliary clearance, the innate immune system is composed of small molecules, proteins, and cells that are able to respond to inhaled particles in a way that does not require any previous exposure to the particle. These molecules are generally highly conserved in evolution and are present in many invertebrate species as well as in humans. They are able to immediately interact with microorganisms through recognition of conserved structures on the microbes, and they can act directly to kill the invader and stimulate a further host immune response. They provide a fast, energy-efficient, effective frontline defense, with broad overlap in actions. There are many components of innate immunity in the lung, and a full description is beyond the scope of this chapter. The interested reader is referred to the in-depth reviews listed in the references. For the reader to get a sense of the system, this chapter focuses on a few of the best described of these molecules: lysozyme, lactoferrin, defensins, collectins (surfactant protein A [SP-A] and surfactant protein D [SP-D]), and immunoglobulin (Ig)A.

Lysozyme is present throughout the respiratory tract but is most prominent in the proximal airways. It is synthesized by respiratory epithelial cells, serous glandular cells, and macrophages. As the name implies, lysozyme causes bacterial cell death by inducing lysis. It is most active against gram-positive organisms. Decreased levels of lysozyme have been correlated with increased susceptibility to acute bronchitis.

Lactoferrin is present in airway fluid. It is produced by serous cells and neutrophils. Lactoferrin acts to agglutinate and kill bacteria, enhance neutrophil adherence, and prime neutrophil superoxide production. Its name derives from the fact that lactoferrin also functions to block iron from supporting bacterial metabolism. Lactoferrin binds to bacteria through recognition of highly conserved carbohydrate moieties on the microbial cell surface.

Defensins are a family of small proteins with intrinsic antimicrobial activity that are found in the lung and on other mucosal surfaces, including the gastrointestinal and reproductive tracts. The two most important types of defensins in the lung are α-defensins and β-defensins. α-Defensins are synthesized by resident neutrophils; β-defensins are made by respiratory epithelial cells. Defensins have broad antimicrobial activity against both gram-positive and gram-negative organisms. They act by making the microbial cell wall permeable, thus causing release of microbial cell contents and destruction of the membrane potential. The activity of defensins is highly sensitive to salt concentrations, and they are inactivated in the abnormal milieu in the lungs of patients with cystic fibrosis.

SP-A and SP-D are members of the collectin family of proteins. Their antimicrobial function is a result of binding and aggregating microbes and facilitating interaction with phagocytic cells. They also appear to be important in regulation of pulmonary macrophage activity and cytokine production. Animal models indicate that defects in either of these proteins increase the susceptibility to respiratory infection; however, human disease related to a genetic mutation or deletion has not been identified.

Respiratory IgA can be considered part of the innate immune system because it is also constitutively produced by the respiratory epithelium and does not require prior exposure. IgA is further discussed in the section on humoral immune mechanisms.

Phagocytic and Inflammatory Cells