Lung Defense Mechanisms

In the process of exchanging thousands of liters of air each day for O₂ uptake and CO₂ elimination, the lung is exposed to a multitude of foreign substances transported with the inhaled air. Some of these are potentially injurious; others are relatively harmless. Inhaled air is not the only source of foreign material. Secretions from the mouth and pharynx frequently are aspirated into the tracheobronchial tree, especially during sleep, even in healthy individuals. This myriad of foreign substances is perhaps best classified into three major categories: small particulate material, noxious gases, and microorganisms. Because the oropharynx is rich with bacteria, aspirated secretions are particularly important as a source of unwanted bacteria entering the airways.

To protect itself against potentially toxic inhaled material, the respiratory system has evolved complex protective mechanisms that can be dissected into different components. Each component appears to have a distinct role, but a tremendous degree of redundancy and interaction exists among different components. That the distal lung parenchyma is normally sterile (and is not in a state of constant inflammation) serves as testimony to the effectiveness of the defense system. However, the protective mechanisms can break down, resulting in respiratory infection. Such a breakdown in defense can occur as a result of certain diseases, a large inoculum of microorganisms that overwhelms a normal host, an especially virulent organism, or frequently as a consequence of medical treatment that impairs the immune system.

Before the discussion of infectious disorders of the respiratory system in Chapters 23 through 26, it is appropriate to first consider how the lung protects itself against the infectious agents to which it is exposed. Although this chapter focuses on protective mechanisms against infection, defenses against noninfectious substances, especially inhaled particulate material, also are addressed. The major categories of defense mechanisms to be discussed include (1) physical or anatomic factors relating to deposition and clearance of inhaled material, (2) antimicrobial peptides, (3) phagocytic and inflammatory cells that interact with the inhaled material, and (4) adaptive immune responses, which depend on prior exposure to and recognition of the foreign material. The chapter concentrates on the aspects of the host defense system specific to the lung and then proceeds with a discussion of several ways the system breaks down, resulting in an inability to handle microorganisms and an increased risk for certain types of respiratory tract infection. The chapter concludes by briefly considering how we can activate or augment specific immune responses through immunization, thus enhancing defenses against selected respiratory pathogens.

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.

Factors affecting deposition and physical clearance of particles are:

1. Particle size

2. Cough

3. Mucociliary transport

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.

Figure 22-1 Schematic diagram of cross-section of cilium. Two central microtubules and nine pairs of peripheral microtubules are shown. Dynein arm projects from each peripheral doublet, and nexin links and radial spokes provide connections within microtubular structure. (From Eliasson R, Mossberg B, Camner P, Afzelius BA: The immotile-cilia syndrome. A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility, N Engl J Med 297:1–6, 1977. Copyright 1977 Massachusetts Medical Society. All rights reserved.)

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.

Airway innate immunity substances include: