Alveolar macrophages are the principal means by which the lungs process the normal burden of inhaled particles. Alveolar macrophages are also secretory and regulatory cells and prevent injurious actions of other lung cells. For instance, it has recently been demonstrated that macrophage engulfment of neutrophils significantly contributes to the resolution of pulmonary inflammation. Once phagocytosis of the ingested particle has been accomplished by alveolar macrophages, the cell and/or toxicant is eliminated by internal digestion or mucociliary transport of the macrophage to the oropharynx. In an additional mechanism, particle-laden macrophages have been shown to traverse the interstitial spaces to reach the mediastinal lymph nodes. Figure 17 demonstrates an airway macrophage beneath the electron-dense lining layer of a rat bronchiole. Airway macrophages are approximately five times more numerous per unit of airway surface area than they are per unit of alveolar surface (Table 4). However, because of the large surface area of the alveolar gas exchange region, alveolar macrophages account for approximately 99% of total air space macrophages.
FIG. 17. Electron micrograph of an airway macrophage beneath the electron-dense lining layer of a rat bronchiole.
TABLE 4. Macrophage distribution and number
Alveolar macrophages are unique mononuclear phagocytes. These cells contain numerous lysosomes in their cytoplasm, consume oxygen and secrete neutral proteases at a high rate, and are more active than other tissue macrophages. Although these cells are individually active, they are poor antigen-presenting cells and poor accessory cells. The primary antigen-presenting cell in the lung is a dendritic cell. The primary role of alveolar macrophages is thought to be in defense of alveoli against dust and pathogens. They appear to be able to carry out this role without activating excessive inflammatory processes in the alveolar septa. The vast majority of antigens reaching the small airways and alveolar septa are processed without activation of lymphocyte-based immune recognition and neutrophils. The lung contains very few lymphocytes in alveolar septa.
Alveolar macrophages arise in bone marrow. There is also an interstitial macrophage pool in the lung, and alveolar macrophages proliferate on the alveolar surfaces. Regeneration of the alveolar macrophage population has been shown to occur in all three of these sites.
Mast Cells
Mast cells are a normal, albeit small, component of lung cells. They are identified by the presence of numerous membrane-bound intracytoplasmic granules with variable intragranular inclusions. These granules are 0.6 to 0.8 µm in diameter. The cells also have long filiform microvilli on the surface. Mast cells have high-affinity IgE membrane-bound receptors that are specific for inhaled allergens. On activation, these cells release allergic mediators, such as histamine, prostaglandin D2 (PGD2) and leukotriene C4 (LTC4). Mast cells also produce neutral proteases (tryptase and chymase), lysosomal enzymes, myeloperoxidase, eosinophil chemotactic factor of anaphylaxis, high-molecular-weight neutrophil chemotactic factor, and heparin. Although the specific role of mast cells is unclear, they clearly play a role in airways secretory and bronchoconstrictor responses of hypersensitivity reactions such as anaphylaxis, hay fever, and asthma. Increased numbers of mast cells are found in pulmonary edema and pulmonary fibrosis.
Neutrophils
Neutrophils are terminally differentiated cells that are distributed in the bone marrow, blood, and tissue compartments. In the normal lung, neutrophils are almost exclusively found within the circulation, and almost half of the total body circulating neutrophils may be marginated along the walls of pulmonary capillaries and venules. Neutrophils are found in significant numbers in the pulmonary tissue spaces only in cases of pulmonary inflammation, such as in the adult respiratory distress syndrome (ARDS). Migration into tissue spaces occurs in response to chemotactic agents produced by invading microorganisms, toxin-derived products, and complement-activated chemoattractants, such as C5. Following phagocytosis, invading organisms are killed within neutrophils by an oxidant-mediated mechanism, by microbicidal proteins contained in neutrophil granules, or both. In the oxidant-mediated process, a membrane-bound NADPH oxidase generates O2–, which can enzymatically or spontaneously dismute to generate H2O2. These species react to form hydroxyl radical, another potent oxidant. These agents individually or in combination kill bacteria. Neutrophil granules contain a host of bactericidal agents, including myeloperoxidase, cathepsin G, acid hydrolases, elastase, and lysozyme.
Eosinophils
Eosinophils are not normally present in lung tissue spaces. However, the presence of significant numbers of these cells and their synthesis products has been shown to occur in allergically induced lung inflammation, and they are believed to play a major role in the development of reactive airways disease.
Eosinophils develop in the bone marrow and are transported via the circulation to the tissue spaces of the gastrointestinal and respiratory tracts. The host defense function is less well defined for eosinophils than for neutrophils. Eosinophils may be capable of some bactericidal activity. However, the principal function of these cells is likely their antiparasitic activity. Eosinophils synthesize and secrete potent inflammatory mediators, such as platelet-activating factor and LTC4.
Innervation of the Lung
Motor neurons in the pulmonary nervous system influence airway tone, pulmonary blood flow, and secretion of mucus. Sensory neurons modulate the cough reflex, the Hering-Breuer reflex, and responses to irritant dusts and gases, and they may respond to interstitial fluid pressure. In addition, a variety of neural peptides released by afferent nerves may modulate airway tone, vascular tone, and airway secretions.
The primary motor and sensory innervation of the lung comes from the vagus nerve (cranial nerve X). In addition, sympathetic fibers arising from the second to the fourth thoracic sympathetic ganglia innervate the lung. Fibers from both the vagus nerve and the thoracic sympathetic plexus comingle as they enter the hilum of the lung and then divide into plexuses that follow bronchi, arteries, and veins. Along the airways, the nerve plexuses lie both internally and externally to the cartilage, with the larger external plexus containing ganglia along the first three bronchial divisions. Nerve fibers continue in airway walls to the level of respiratory bronchioles.
The arterial nerve plexus travels in the media and distally reaches the full extent of muscular arterioles. The venous nerve plexus reaches all the way to the visceral pleura and even supplies subpleural alveolar walls.
In addition, small unmyelinated nerve fibers have been identified in alveolar walls. They are rare, and their source has not been clearly identified. These fibers are thought to represent J (juxtacapillary) receptors, which in animals have been shown to respond to interstitial fluid pressure and certain chemicals. They cause a transitory reflex apnea and shallow rapid respiration.
The primary motor innervation for the lung is parasympathetic (cholinergic). Stimulation of the vagus nerve leads to bronchoconstriction and enhanced secretion of mucus. These actions are blocked by atropine. Parasympathetic nerves arising from the vagus nerve synapse in the ganglia of the first generations of intrapulmonary bronchi. The primary neural inhibitor of bronchial muscular tone is vasoactive intestinal peptide (VIP). This neuropeptide is stored and released by parasympathetic neurons and may coexist with acetylcholine. Thus, the same group of neurons may release acetylcholine, which contracts airway smooth muscle, and VIP, which counteracts the action of acetylcholine to act as a bronchodilator. There are multiple examples of neurotransmitters with opposing actions being released from common nerve elements in the lung; for example, neuropeptide Y, a bronchial and vascular constrictor, coexists in pulmonary adrenergic nerves with norepinephrine. The complex interactions of the parasympathetic, sympathetic, and nonadrenergic, noncholinergic (NANC) nervous systems in the lung and the coexistence of opposing neurotransmitters has made the study of neural control of lung function difficult. It is clear, however, that motor innervation of the airways is predominantly parasympathetic and that there is no significant direct adrenergic innervation of bronchial smooth muscle.
The NANC nerve supply to the lung is thought to regulate primarily mucous secretion and bronchial blood flow. NANC nerves can be either inhibitory or excitatory, and their function is not yet well characterized. The inhibitory functions include relaxation of bronchial smooth muscle, perhaps by the release of nitric oxide or VIP. VIP is a potent relaxant of human bronchi in vitro but appears to have little effect on smaller airways. Excitatory responses of the NANC system include bronchoconstriction, possibly mediated by the release of tachykinins, such as substance P. By means of neural stains and electron microscopy, unmyelinated nerve fibers have been shown to pass through the airway epithelial basement membrane and be distributed between columnar bronchial epithelial cells. These fibers contain neuropeptides thought to be released as a reflex response to activation of local irritant receptors. The major neuropeptides identified in the lung are shown in Table 5. In addition, Kultschitsky neuroendocrine cells may play a role in afferent nerve function. These cells have been found to release neuroactive peptides, including serotonin, calcitonin, and bombesin.
TABLE 5. Neuropeptides in the human lung
Neural control of the pulmonary vascular system has been a substantial area of investigation. Despite this, the role of the nervous system in regulating blood flow in the human lung is not well understood. Nerves arising from both the sympathetic and parasympathetic systems innervate the pulmonary vascular system. In most animals, adrenergic supply of the pulmonary arterial system predominates over cholinergic innervation. Electric stimulation of the nerves of the lung has been shown to cause both vasoconstriction and vasodilation. Pulmonary arterioles are thought to be the primary site for pulmonary vascular resistance. The pulmonary venous system is well innervated and may also play a role in regulating resistance and capacitance of the pulmonary vascular system. Sympathetic stimulation in animals has been shown to cause pulmonary venous constriction.
The sensory system in the lung travels upward through both the vagus nerve and the thoracic sympathetic plexus. Receptors in the main bronchi mediate the cough reflex. Small airways contain irritant receptors that respond to irritant gases, irritant dust, and mechanical stimuli to produce bronchoconstriction, hyperventilation, and chest discomfort. The Hering-Breuer reflex involves mechanoreceptors located in airway walls. These receptors increase their rate of firing under stretch and thus inhibit the central inspiratory center as a progressive reflex response to lung expansion. The nerves mediating this reflex are thought to be located in the smooth muscle of the bronchial walls.
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