Although pulmonary tracheobronchial epithelial and alveolar epithelial cells are not normally considered 'phagocytic,' uptake of exogenous particles by these cells appears to be a universal phenomenon. One might ask, in this circumstance, whether particle uptake is really a protective mechanism 'designed' to remove particles from the airways and alveoli in much the same way as the macrophage response removes particle. However, it is hard to see a protective mechanism in a process that commonly (at least in the hands of experimentalists) produces damage to membranous, cytoplasmic, and genomic cell contents; that appears to be associated with carcinogenic events; that may be associated with morbidity and mortality from particulate air pollutants; and that, with sufficient particle dose, culminates in airway wall and/or interstitial fibrosis. In a teleologic sense, it would appear far better to remove all particles by macrophage phagocytosis than to allow epithelial uptake to occur. Indeed, Lehnert (2) suggests that persisting free particles in air spaces reflect what he labels poor 'fidelity' of macrophage- mediated particle removal from the lung, implying, again in a teleologic sense, that persistence of free particles, and therefore opportunities for particle entry into epithelial cells, are by accident rather than by design. The fact that every type of particle is taken up by pulmonary epithelial cells does not change this conclusion but merely points out that different types of particles have different degrees of intrinsic toxicity, and that particle dose also has a major role in shaping response. It is clear that the most important determinant of uptake is free particle persistence on the airway surface or in the alveolar space; particles that are not rapidly removed by the mucociliary escalator or by macrophages are likely to enter epithelial cells. In a very broad sense there is a dose response between the numbers of particles reaching the airways and air spaces and the numbers of particles entering epithelial cells, although this dose response really has a threshold because below the particle number (volume/mass) level at which overload is created, most particles are cleared from the lung and few enter epithelial cells; once overload is achieved and macrophage egress from the lung is impaired, particle uptake increases with dose, probably in an exponential fashion. These general conclusions hide major gaps in our knowledge of the factors controlling particle uptake. These gaps can be summarized quite simply by stating that there are marked and unexplained differences in the uptake of different types of particles, and that there is little knowledge about the actual mechanics of particle uptake. It appears that there are major differences in the rate and the extent to which different types of pulmonary epithelial cells take up particles; for example, type II cells appear to engulf relatively few particles compared with type I cells, and airway mucous cells take up fewer particles than do ciliated cells, but these conclusions are based on very few quantitative data. It has been proposed that smaller particles are taken up much more readily than larger particles, but the experiments from which this conclusion is drawn are confounded by use of much greater numbers of small than of large particles, as well as by difficulties of interpretation of data from complex (multivariable) in vivo systems. There are few and often contradictory data on the relative uptake of short compared with long fibrous minerals, even though long fibers in general are believed to be considerably more pathogenic than short ones. Thus, although it is likely that particle size is a major determinant of particle uptake, it is difficult to state categorically what the effect of size might be. Particles have been demonstrated to bind to tracheobronchial epithelial cells in organ culture explants, and they presumably bind to alveolar epithelial cells as well, although no direct data exist on this latter point. The mechanism of binding is uncertain; it has been suggested that positively charged particles bind to sialic acid residues on the apical membrane, and that negatively charged particles bind through fibronectin or vitronectin coating of the particle with subsequent adherence to the RGD receptor. In some experiments, artificial manipulation of particle charge changes binding and also cytotoxicity. However, the notion that all binding of negatively charged particles occurs via adhesion proteins is probably not correct. Active oxygen species, specifically hydrogen peroxide and probably hydroxyl radical, appear to play a role in particle uptake, and scavenging active oxygen species reduces but does not completely inhibit uptake of asbestos fibers. Iron on the particle surface is probably crucial to this process, and artificially increasing surface iron increases particle uptake. The normal production of small amounts of hydrogen peroxide by pulmonary epithelial cells may in fact serve as an accidental autocrine mechanism by which particle uptake is increased, and release of AOS from particle-evoked inflammatory cells may well have the same effect. Exogenous sources of AOS such as cigarette smoke and ozone clearly enhance uptake and probably potentiate mineral-dust-induced pathologic reactions.
