For the exchange of gases, conditioning of inspired air, and defense against inhaled toxicants to be accomplished simultaneously, highly synergistic interactions between respiratory tract clearance and secretion and biochemical and cellular defense mechanisms are required. In the normal lung, defense functions are mediated by epithelial cells of the airways and alveolar regions, resident alveolar macrophages, and numerous proteins in the extracellular spaces and mucous lining layers. Resident lung macrophages carry out the normal tasks of lung defense by selective phagocytosis of foreign particles; secretion of proteases, oxygen free radicals, and cytokines; and antigen presentation. In the presence of toxicants or other pathologic conditions, infiltration of bloodborne phagocytes, such as neutrophils, and toxicant-specific immunologic mechanisms, such as antibody production by B lymphocytes and cellular cytotoxic actions by T lymphocytes, augment the normal defense functions. Inflammatory cells recruited into the lungs tend to produce indiscriminate injury to resident lung cells and tissues by nonselective release of proteases, oxygen free radicals, and other cytotoxic agents. The lung appears to be designed to clear normal levels of inhaled pollutants without activating these inflammatory patterns, but it can activate them when more severely stressed.
Deposition of Inhaled Gaseous Toxicants
Because the physical mechanisms of transport and chemical uptake vary significantly between different airborne toxicants, no single approach can be used to estimate the pulmonary uptake of all inhaled agents. For instance, formaldehyde and ozone are both highly reactive gaseous toxicants with an inspiratory uptake of greater than 90%. However, the solubility of formaldehyde in aqueous biologic solutions is approximately 12 times greater than that of ozone. Because of their different solubilities, the critical target sites of injury for formaldehyde and ozone are at opposite ends of the respiratory tract. The major sites of uptake and toxic reactions of formaldehyde are in the nose and other parts of the upper respiratory tract. The uptake of formaldehyde in the upper respiratory tract is so rapid that virtually none of it reaches the lower respiratory tract. In contrast, because of the lower solubility of ozone, more of it reaches the lower respiratory tract. Significant uptake of ozone does occur in the nasal passages and upper respiratory tract; however, this uptake is associated with reaction of ozone with components of the thick mucous layer lining this region. The site of greatest injury from inhalation of ozone, and similar oxidant gases, is the alveolar epithelium at the transition between airways and the gas exchange region. In this region, the surface lining fluids are thin, so that the probability of ozone reacting directly with the underlying alveolar epithelial cells is greater. The critical respiratory targets and the toxic responses to all airborne pollutants depend on their inhaled concentrations, the resulting concentration gradient in different regions of the respiratory tract, and the effects of scrubbing and/or detoxification of the reactive gas by the mucous lining layer overlying the epithelial layer in each region.
Deposition of Inhaled Particles
The alveolar septal region is continually bombarded by a variety of organic and inorganic materials ranging from transition metals to animal and human proteins. Although the upper respiratory tract and upper airways filter most inhaled particulate matter, it is well documented that particles of 1 µm in size are not effectively filtered by the upper respiratory tract and that a significant fraction of these particles deposit on the intrapulmonary airways or reach the alveolar region. Normal ambient air can contain on the order of 10,000 respirable particles, defined as less than 10 µm in size with a mass median aerodynamic diameter (MMAD) of 0.3 µm, per cubic centimeter. Up to 30% of these particles deposit on medium and small airways, and about 10% deposit in the alveolar region. Thus, if a minute ventilation of 10 L is assumed, 30 million particles deposit per minute on smaller airways and 10 million particles deposit per minute on alveoli and alveolar ducts. Although the human lung contains 500 million alveoli, the particles tend to deposit proximally, and the load can be estimated to be up to one particle per minute per alveolus in the proximal alveolar ducts. The lung handles this steady, normal load of particulate matter without inducing inflammatory amplification.
These same pollutants would cause a strong inflammatory reaction if injected into another organ, yet they appear to cause virtually no reaction in alveolar septa in normal lungs. This is remarkable when one considers that the alveolar-capillary gas exchange membrane in most regions is thinner than 1 µm. If the organic and inorganic materials reaching the airways and alveolar surface were to stimulate the type of inflammatory reactions that occur in many other tissues, white cells would be rapidly recruited into these spaces and a progressive inflammation would result, leading to acute bronchitis, acute alveolitis, and/or interstitial fibrosis. The absence of an injurious response to normal lung particle burdens appears to be the result, in part, of the unique role of resident lung defense cells, such as alveolar macrophages. Each alveolus contains an average of 12 macrophages, which are thought to process all particles reaching this region under normal conditions. Alveolar macrophages have been shown to have a blunted capacity for antigen presentation and mitogen production compared with other monocytic phagocytes, and thus they are able to process inhaled particles without stimulating excessive immunologic responses or lung inflammation. The lipids and/or proteins of the alveolar surface lining layer have been shown to have anti-inflammatory actions. High particle loads given experimentally have been shown to overload these and other anti-inflammatory defense mechanisms and induce alveolar inflammation. The dose-response relationship for the onset of particle-induced inflammation is not known, nor are the mechanisms controlling this process.
Pulmonary disorders in which particle deposition and/or clearance plays a major role include hypersensitivity pneumonitis, silicosis, asbestosis and other mineral fiber disorders, and a number of metal- and organic antigen-specific disorders. In most of these cases, the biologic association between toxicant dose and health effects has been clearly demonstrated.
Epidemiologic studies demonstrate a significant association between particulate exposure and increases in hospital admissions, morbidity, and mortality. Children, whose small airways are potentially more susceptible to particle-induced inflammation and limitations of air flow, are thought to be at high risk. Airborne particulate levels as low as 150 µg/m3 are statistically associated with increases in elementary school absenteeism. The association between particle concentration and increased mortality appears to be maximal when the experimental results are averaged over a 3- to 5-day period. Such studies have been the primary means of identifying human health risks associated with particle inhalation. These studies taken as a whole suggest that ambient levels of particles on the order of 100 µg/m3 are associated with adverse health effects. Each increase of 10 µg/m3 in the PM10 (particulate matter with an aerodynamic diameter of 10 µm) is associated with an approximate 1% increase in mortality. The increased mortality appears to occur largely among the sick and elderly. The underlying biologic mechanisms responsible for these epidemiologic associations have not been determined. Interactions between particles and other pollutants, such as sulfur dioxide and nitrogen dioxide, and the effects of climate have been suggested as critical factors. High levels of trace metals in the particulate matter from urban and industrial sources have been suggested as possible causative agents. Table 6 illustrates the significant differences that exist in trace element composition between air sampled at a remote natural site and in various North American cities. In cities with a large number of anthropogenic sources, the potentially toxic trace elements of nickel, copper, and zinc are present at substantial levels. Particle samples from natural sites that are not contaminated by anthropogenic sources do not contain significant levels of these elements.
TABLE 6. Comparison of ambient dust concentrations
Deposition of inhaled particles occurs according to physical mechanisms of inertial impaction, gravitational sedimentation, diffusion, and interception. A variety of factors, such as aerosol particle size, density, shape, hygroscopic/hydrophobic character, and electrostatic charge, may also play important roles in determining how these mechanisms control the location and efficiency of deposition in the lungs. Because particles are present in a range of sizes and shapes, an aerosol is typically described by a size distribution or a mass/count weighted mean. In toxicologic evaluations, the Mass Median Aerodynamic Diameter (MMAD) is typically used to describe an aerosol in terms of the aerodynamic behavior of its particles, site(s) of particle deposition, and deposited mass. Particles in the size range of 1 to 10 µm deposit with relatively high efficiency in the upper respiratory tract and large airways, where inertial deposition is driven by high flow rates. Particles in the size range of 0.01 to 0.1 µm deposit by diffusion and are primarily taken up in the alveolar regions, where the large surface area enhances deposition by diffusion and sedimentation. The small airways do not have a single dominant mechanism of deposition.
Both empiric and mathematical approaches have been used to assess the dosimetry of inhaled particles. Direct measurements of deposition demonstrate that the human upper respiratory tract efficiently removes particles with an Mass Median Aerodynamic Diameter (MMAD) of approximately 5 µm. For particles in the 1- to 5-µm range, the total respiratory tract (upper respiratory tract plus conducting airways plus gas exchange region) deposition efficiency is on the order of 20%. Mathematically based estimates of the alveolar deposition efficiency of inhaled 1- and 5-µm aerosol particles are 5.2% and 17%, respectively.
Because of the nature of the mechanisms of deposition, deposited particles are not uniformly distributed on respiratory tract surfaces. Aerosols have been shown to deposit preferentially on the ridges of airway bifurcations, both in theoretical models and in direct observation of aerosol behavior using airways casts. Experimental observations of ciliary activity and mucous flow suggest that the concentration of particles on the ridges of airway bifurcations could, in part, result from trapping of particles on these ridges as they are cleared from more distal airways. Particles on airway ridges or branch points are cleared with a half-life of approximately 1 hour.
Particles deposited in the airways are rapidly cleared by the mucociliary escalator and by airway macrophages. Within 24 hours, most particles with a diameter of 1 µm are cleared from the airways. Particles initially deposited in the alveolar region are primarily cleared by macrophage phagocytosis. Clearance from the alveolar region is considerably slower than clearance from the airways, and removal of insoluble particles may require weeks to months.
Immunologic Responses
Immunologic responses can be classified as nonspecific or innate immune responses (actions of macrophages, monocytes, lymphocytes, and granulocytes) or agent-specific immune responses (immunologic memory of T and B cells). The innate defense mechanisms include a combination of phagocytosis and cytotoxic effects by effector cells and activation of the complement cascade. In the adaptive response, a large population of antigen-specific lymphocytes is produced that results in a potentially greater and prolonged immune system response. The adaptive response occurs when an antigen derived from the toxicant exposure is processed and presented by a dendritic cell, macrophage, or monocyte to a lymphocyte. The lymphocyte then undergoes clonal expansion to produce large numbers of cells that are specific for the particular toxic agent. Cytotoxic T-cell production occurs by this process when major histocompatibility (MHC) is expressed by the antigen-presenting cells in association with toxicant-derived antigen. Activated T cells produce numerous cytokines, such as tumor necrosis factor, that significantly enhances the immune response and the inflammatory responses of resident lung cells. Antibodies specific to the antigen are produced by B cells, which are stimulated by the interleukins to produce memory cells and plasma cells.
The effects of inhaled particles on human health are likely to involve inflammation, hypersensitization, and immunologic memory of T and B cells. These mechanisms are capable of amplifying injury initiated by repeated, low-dose exposures to antigens and therefore have the potential to produce significant effects at ambient levels of exposure. The pulmonary immune system differs from the systemic immune system in its ability to produce localized cell-mediated immune responses on repeated exposure to inhaled antigenic materials. Such localized response may play a significant role in hypersensitivity pneumonitis. Particles that contain metals have been shown to produce these responses. For instance, nickel and other transition metals are highly toxic and known to produce delayed hypersensitivity. Recent studies indicate that T-cell recognition of metal-complexed haptens plays a role in T-lymphocyte immune responses.
The airway epithelium and the alveolar epithelium are the primary lung surfaces on which inhaled toxicants may be initially distributed and/or react. The airway epithelium is a likely critical target site for an inhaled toxicant, as it is the first cellular barrier to inhaled toxicants and the most densely populated of the target surfaces. These aspects are offset to a large extent by the protection afforded by the thick mucous layer overlying airway epithelial cells and the efficient ciliary propulsion system. The alveolar epithelium of the gas exchange region has a large surface with a relatively low density of cells covered by a thin surface film. The thin surface film of the alveolar epithelial layer constitutes a critical site of possible action for pollutants not filtered by proximal airways. The outermost region of the respiratory path is the pleura, and this site is typically involved in toxic processes only after secondary transport following initial uptake of the reactive substance in more proximal air spaces. At each level, the presence or absence of adverse effects of inhaled particles and reactive gases is primarily determined by the unique immune response system in the lung.
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