section. Superficial to the sol layer is the more viscous gel layer, which is produced by both submucosal mucous glands and goblet cells. The viscous gel layer floats on top of the sol layer and is propelled in a cephalad direction as the cilia 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 capable of responding 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 pattern recognition receptors that are stimulated by conserved structures on microbes, and they can act directly to kill the invader and initiate an additional host immune response. The innate immune response provides a fast, energy-efficient, effective frontline defense, with broad overlap in actions. There are many components of innate immunity in the lung and more than 2000 naturally occurring antimicrobial peptides. A full description is beyond the scope of this chapter; however, the interested reader is referred to the in-depth reviews listed in the Suggested Readings. 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:
1.Lysozyme
2.Lactoferrin
3.Defensins
4.Collectins (surfactant proteins A and D)
5.IgA
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 the 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. Two 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
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potential. The activity of defensins is highly sensitive to ionic 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 the regulation of pulmonary macrophage activity and cytokine production. Animal models indicate that defects in either of these proteins increase the susceptibility to respiratory infection.
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 “Humoral Immune Mechanisms” section.
Phagocytic and inflammatory cells
Pulmonary alveolar macrophages
In the airways and at the level of the alveoli, particles and bacteria can be scavenged by mononuclear phagocytic cells called pulmonary alveolar macrophages. These cells constitute a major form of defense against material that has escaped deposition in the upper airway and has reached the intrathoracic airways or the alveolar structures.
Pulmonary alveolar macrophages are large mobile cells approximately 15 to 50 μm in diameter. They are descendants of circulating monocytes derived from bone marrow. These cells adhere to the alveolar epithelium. Their cytoplasm contains a variety of granules of various shapes and sizes, many of which are packages of digestive enzymes that can dispose of ingested foreign material. Alveolar macrophages have a major role in killing microorganisms that have reached the lower respiratory tract. They also release chemoattractant cytokines (chemokines) that recruit other inflammatory cells.
When an alveolar macrophage is exposed to inhaled particles or bacteria, attachment of the foreign material to the surface of the macrophage is the first step in the processing sequence. The particles or bacteria are engulfed within the plasma membrane, which invaginates and pinches off within the cell to form a cytoplasmic phagosome containing the now isolated foreign material. In some circumstances, this sequence of attachment and phagocytosis is facilitated by opsonins, which coat the foreign material. Opsonins are proteins that bind to extracellular materials and make them more adherent to phagocytic cells and more amenable to engulfment or ingestion. Opsonins can be specific for the particular foreign substance, such as antibodies directed against antigenic material, or they may demonstrate nonspecific binding to a variety of substances. Particularly important specific opsonins are antibodies of the IgG class directed against antigenic foreign material, either bacteria or other antigenic particles. Nonspecific opsonins in the lung include secretory IgA, complement, and fibronectin. All these opsonins greatly promote attachment to and ingestion by macrophages.
After bacteria or other foreign material is isolated within phagosomes, a process of intracellular digestion occurs within the macrophage. Often the phagosomes combine with lysosomes to form phagolysosomes, in which proteolytic enzymes supplied by the lysosome digest, detoxify, or destroy the phagosomal contents. In addition to lysosomal enzymes, a variety of oxidation products, such as hydrogen peroxide and other intermediate products of oxidative metabolism, are toxic to bacteria and play a role in the ability of the macrophage to kill ingested microorganisms.
After they are activated, the resident pulmonary macrophages participate in orchestrating further immune responses. Macrophages release inflammatory mediators such as tumor necrosis factor-α and interleukin-1β, as well as other cytokines and chemokines that are active in recruiting additional inflammatory cells.
The macrophage does not always kill or totally eliminate inhaled foreign material to which it is
exposed. In some cases, such as with inhaled silica particles, the ingested material is toxic to the macrophage and eventually may kill the phagocytic cell. In other cases, ingested material is inert but essentially indigestible and may persist indefinitely in the form of a residue that cannot be broken down further or cleared. Some organisms are especially capable of persistent infection of macrophages without being killed or deactivated, including Mycobacterium tuberculosis and the human immunodeficiency virus (HIV).
Alveolar macrophages are also important in suppression of inflammation in the lung. The lung is unique in that it is constantly exposed to inhaled foreign substances but at the same time must maintain an exquisitely delicate gas-exchange apparatus. Even a small amount of inflammation within the alveolar wall would have a negative effect on gas exchange, and a fine balance keeps the distal airways free of infection but not in a state of constant harmful inflammation. Alveolar macrophages are able to process a large amount of inhaled substances without inciting an immune response external to the macrophage itself. It is estimated that the normal pool of alveolar macrophages can handle up to 109 inhaled bacteria before the bacteria overwhelm the macrophages and cause infection in the alveoli. In addition, alveolar macrophages, through complex signaling mechanisms, function to keep dendritic cell and T-cell activation in check. The detailed working of this fine equilibrium between inflammation and quiescence in the lung is an area of active research.
Major phagocytic and resident inflammatory cells:
1.Pulmonary alveolar macrophages
2.Dendritic cells (airway and parenchymal)
3.Polymorphonuclear leukocytes
4.Natural killer cells
Dendritic cells
Dendritic cells are present throughout the body in various forms. They are bone marrow–derived cells that, in the lung, are located in the airway epithelium as well as in alveolar walls and peribronchial connective tissue. These cells have long and irregular cytoplasmic extensions that form a contiguous network. The primary function of dendritic cells is to sample the airway microenvironment, ingest and process antigens, and then migrate to regional lymph nodes. In the lymph nodes, dendritic cells present antigen to T cells, a critical step for the later immunologic defense provided by lymphocytes. Langerhans cells, a type of dendritic cell with a particular ultrastructural appearance, are the cells with abnormal proliferation that appear to be responsible for Langerhans cell histiocytosis of the lung (also called eosinophilic granuloma; see Chapter 11).
Polymorphonuclear leukocytes
Another important cell involved in pulmonary defense is the polymorphonuclear leukocyte (PMN). The PMN is a particularly important component of the defense mechanism for an established bacterial infection of the lower respiratory tract. Normally, few PMNs reside in the small airways and alveoli. When bacteria overwhelm the initial defense mechanisms already discussed, they may replicate within alveolar spaces, causing a bacterial pneumonia. Examination of the histologic features of a bacterial pneumonia reveals that a prominent component of the inflammatory response is an outpouring of PMNs into the alveolar spaces. These cells probably are attracted to the lung by a variety of stimuli, particularly products of complement activation and chemotactic factors released by alveolar macrophages.
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The eventual movement of PMNs out of the vasculature and into the lung parenchyma depends on the initial adherence of PMNs to the vascular endothelium. A variety of factors mediate this process of adhesion, including integrins (on the surface of the PMNs) and adhesion molecules (on the surface of the vascular endothelial cells).
When PMNs are involved, they play a crucial role in phagocytosis and killing of the population of invading and proliferating bacteria. Neutrophil granules contain several antimicrobial substances, including defensins, lysozyme, bacterial permeability–increasing protein, and lactoferrin. In addition, neutrophils can generate products of oxidative metabolism that are toxic to microbes.
Natural killer cells
Natural killer (NK) cells are part of the rapid initial response and are capable, without prior sensitization, of killing cells infected by microorganisms, particularly viruses. NK cells lack surface markers characteristic of either T or B lymphocytes (discussed in the “Cellular Immune Mechanisms” section). They act by recognizing and killing virus-infected cells that have been transformed and express different markers of cellular health on the cell surface. NK cells also are important in surveillance for neoplasms, and they use the same methods to detect and kill malignantly transformed cells.
Adaptive immune responses
The final category of defense mechanisms for the respiratory system is the adaptive immune response, which involves recognizing and responding to specific antigenic material after prior sensitization. Bacteria, viruses, and other microorganisms are perhaps the most important antigens to which the respiratory tract is repetitively exposed. Presumably, immune defense mechanisms are particularly important in protecting the individual against these agents. The processes of the adaptive immune response are not unique to the lung, and only a superficial discussion of general principles is provided here as a basis for understanding the adaptive immune responses in the lung. For more detailed information, the reader is referred to specialized texts and review articles on immunology.
The two major components of the adaptive immune system are humoral (or B-lymphocyte related) and cellular (or T-lymphocyte related). Humoral immunity involves the activation of B lymphocytes (which do not require the thymus for differentiation) and the production of antibodies by plasma cells (which are derived from B lymphocytes). Cellular immunity refers to the activation of T lymphocytes (which depend on the thymus for differentiation) and the execution of certain specific T-lymphocyte functions, including the production of soluble mediators or cytokines. The two lymphocyte systems are not independent of each other. In particular, T lymphocytes appear to have an important role in regulating immunoglobulin or antibody synthesis by the humoral immune system.
Both humoral and cellular immunity are important in the protection of the respiratory system against microorganisms. For certain infectious agents, humoral immunity is the primary mode of protection. For other agents, cellular immunity appears to be paramount. In the lung and in blood, T lymphocytes are more numerous than B lymphocytes, but both systems are essential for effective defense against the spectrum of potentially harmful microorganisms.
Lymphocytes can be found in many locations within the respiratory tract, extending from the nasopharynx down to distal regions of the lung parenchyma. True lymph nodes are present around the trachea and carina, and at the hilum of each lung in the region of the mainstem bronchi. These lymph nodes receive lymphatic drainage from most of the airways and lung parenchyma. Lymphoid tissue is present in the nasopharynx, and collections of lymphocytes arranged in nodules are found along medium to large bronchi. These latter collections are called bronchus-associated lymphoid tissue and may be responsible
for intercepting and handling antigens deposited along the conducting airways. Smaller aggregates of lymphocytes can be found in more distal airways and even scattered throughout the pulmonary parenchyma.
Major components of the adaptive immune system operative in the respiratory tract:
1.T lymphocytes
2.B lymphocytes
3.IgG
Humoral immune mechanisms
Humoral immunity in the respiratory tract appears in the form of two major classes of immunoglobulins: IgA and IgG. Antibodies of the IgA class are particularly important in the nasopharynx and upper airways, where they constitute the primary antibody type. The form of IgA present in these areas is secretory IgA, which includes a dimer of IgA molecules (joined by a polypeptide) plus an extra glycoprotein component termed the secretory component. Secretory IgA appears to be synthesized locally, and the quantities of IgA are much greater in the upper respiratory tract than in the serum.
Evidence suggests that secretory IgA plays an important role in the respiratory defense system. By virtue of its ability to bind to antigens, IgA may bind to viruses and bacteria, preventing their attachment to epithelial cells. In addition, IgA is efficient in agglutinating microorganisms; the agglutinated microbes are more easily cleared by the mucociliary transport system. Finally, IgA appears to have the ability to neutralize a variety of respiratory viruses as well as some bacteria. Nonetheless, many of the functions of IgA are redundant with other parts of the immune system, as the majority of individuals with selective IgA deficiency are asymptomatic, whereas fewer than 10% develop recurrent sinopulmonary infections.
In contrast to IgA, IgG is particularly abundant in the lower respiratory tract. It is synthesized locally to a large extent, although a fraction also originates from serum IgG. It has a number of biological properties, such as agglutinating particles, neutralizing viruses and bacterial toxins, serving as an opsonin for macrophage phagocytosis of bacteria, activating complement, and causing lysis of Gram-negative bacteria in the presence of complement.
The overall role of the humoral immune system in respiratory defenses includes protecting the lung against a variety of bacterial and, to some extent, viral infections. The clinical implications of this role and the consequences of impairment in the humoral immune system are discussed in the “Defects in the Adaptive Immune System” section.
Cellular immune mechanisms
Cellular immune mechanisms, those mediated by thymus-dependent (T) lymphocytes, also operate as part of the overall defense system of the lungs. Sensitized T lymphocytes produce a variety of soluble, biologically active mediators called cytokines, some of which (e.g., interferon [IFN]-γ) function to attract or activate other protective cell types, particularly macrophages. T lymphocytes also can interact with the humoral immune system and modify antibody production.
Two important types of T lymphocytes have been well characterized based on specific cell surface markers and functional characteristics. One type consists of cells that are positive for the CD4 surface marker, commonly called CD4+ or helper T cells. CD4+ cells, in turn, are divided into TH1 and TH2 subsets, which mediate cellular immune defense and allergic inflammation, respectively. The other major
type of T lymphocyte consists of cells that are positive for the CD8 surface marker. These CD8+ cells
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