Rats were exposed to quartz dust (about 90 mg/m3) for five hours a day, five times a week either throughout the 48 weeks of the experiment or for a total of 40 weeks plus eight weeks of "rest."Cytological study of bronchoalveolar lavage showed that at a certain level of silicotic changes in the lungs, a pronounced breakdown in pulmonary dust clearance by macrophages could be observed. There was, however, a concomitant compensatory increase in the contribution to pulmonary phagocytosis by the neutrophil leukocytes (NL). As a result, pulmonary dust kinetics could be mathematically described using a constant clearance rate both throughout the 48 weeks of exposure and during the eight weeks after the end of the 40 week exposure. It is shown in a separate experiment that enhanced recruitment of NL into the airways may be due not only to an attractant effect of the products of macrophage breakdown (PMB) themselves but also to the release of an NL attractant factor by viable macrophages activated under influence of the PMB.
A multicompartmental model for the kinetics of dust retention in the pulmonary region of the lung and in the tracheobronchial lymph nodes has been developed. The model reflects the following ideas concerning the basic features ofthis process: (1) penetration into the pulmonary interstitium and translocation to the lymph nodes are possible for nonphagocytised particles only; (2) these processes depend on the degree of damage to macrophages by dust and on the extent of compensatory enhancement in the recruitment of neutrophils taking part in the clearance of the pulmonary region free surface; (3) a certain proportion of initially penetrating particles is continuously returned to this surface together with recruited pulmonary macrophages. The model ensures a satisfactory approximation to experimental data on the retention ofquartz in the lung and lymph nodes during long term inhalation exposure, and simulation of the kinetic effects associated with both the damage to and the protection of the macrophagal clearance mechanism.Various mathematical models for the kinetics of deposition and retention of dust in the lung are usually proposed as a basis for predicting "the accumulation of lung burden during prolonged chronic exposure relevant to the exposure of workers to mineral dusts in a wide range of industries"' and, thus, as an instrument for "exposure assessment for occupational epidemiology".23Another Modelling the kinetics of the deposition and retention of particles in the "deep lung" (meaning the region that was called "pulmonary" by the ICRP Task Group on Lung Dynamics4 and many other authors) Vincent et al considered two mutually independent compartments of "medium" and "slow" clearance; the third compartment (of "fast" clearance) corresponded to the tracheobronchial region. The model, however, does not account for the physiological mechanisms that determine the differences in the rate of clearance of the compartments, and its structure is not claimed to describe actual relations between them.Most investigators (for example5) identify the rapidly removed part of dust deposited in the pulmonary region as that which is removed directly from the free surface ofthe acinus towards the mucociliary escalator, and the slowly removed part as that which has already penetrated into the "fixed tissues" (into the lung interstitium). Thus in both the route of deposition and the route of elimination, real compartments of dust in the "deep lung" are connected in series rather than in parallel as in the model.'One ofthe variants ofthis model assumes a sudden and complete failure of the medium clearance compartment and, therefore, transfer of all material into the slow clearance compartment. In another variant of the same model, both compartments have parallel exits not only to the mucociliary escalator but also to some intralung kinetic trap that has no exit at all. Like the basic model,' both of these variants ensure a
The cytotoxic action of quartz (DQ12) particles on cultures of rat peritoneal macrophages, as estimated by the inhibition of the TTC-reductase activity, is considerably reduced by preincubation with glutamic acid and by adding sodium glutamate (15 mg/ml) to the drinking water of the rats donating the macrophages. This increase in macrophage resistance under the influence of glutamate is the most probable cause of the delay in the development of silicotic fibrosis shown in several experiments on rats intratracheally injected with quartz and then treated by prolonged administration of glutamate. This effect is probably connected with the influence of glutamate on the stability of the macrophage membranes, which can in its turn be explained by different mechanisms, including the influence on the synthesis and phosphorylation of adenosine nucleotides. Such an influence was shown in rats receiving glutamate by the change of the ATP/ADP ratio in macrophages, but not in erythrocytes. The resistance of rat erythrocytes to the haemolytic action of quartz is also not influenced by the action of glutamate neither in vitro nor in vivo. Such differences in the influences of glutamate on two types ofcells, equally susceptible to quartz cytotoxicity but considerably differing in the character of energy metabolism, is an indirect proof of the role of the latter in the realisation of the anticytotoxic, and thereby antifibrogenic, effect of glutamate.It is known that the high fibrogenicity of silica dusts is connected with their high cytotoxicity for macrophages whose breakdown is accompanied by the formation of some factor that stimulates the synthesis of collagen and interferes with the normal interaction between macrophages and fibroblasts that plays an important part in the regulation of fibrogenesis.1-6 It is not by chance that the first encouraging successes in the experimental treatment and prophylaxis of silicosis were obtained 20 years ago with polyvinylpyridine-N-oxide7-9 and later also with other nitrogen-containing polymer compounds,10-15 whose mechanism of action is connected with the defence of macrophage from the cytotoxicity of silica particles. The key role of this cell in the elimination of dust particles from the alveolar region makes its protection from damage a most important factor in the prophylaxis of silicosis. In fact, polyvinylpyridine-N-oxide stimulates the elimination of quartz dust from the lungs and decreases its retention and penetration.8 9 Nevertheless, the possibilities of the therapeutic, prolonged retention in the organism, and doubts as to their harmlessness. Data on the possible carcinogenic effects of polyvinylpyridine-N-oxidel6 cause some anxiety. Therefore, despite the fact that our laboratory (as seen from the references above) continues the search for highly effective, but less toxic, antisilicotic nitrogen containing polymers, it was but natural to develop research directed at the same link in silicosis pathogenesis but with the use of more physiological means of increasing ...
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