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Biomedical subjects

A G Heppleston

Publications and source records attributed to A G Heppleston.

At least 19 recordsLinked to original sources
PubMed1992

Coal workers' pneumoconiosis: a historical perspective on its pathogenesis.

The earliest observations on coal workers' pneumoconiosis identified fundamental factors and posed particular problems in its genesis. Among the former, intensity of exposure and particle size were recognized, while argument commenced on the roles of stone dust, thus anticipating the quartz question, and of complicating pulmonary states, which introduced the idea of infection. Major studies of the disease were precipitated by its greatly increased prevalence, which became evident among South Wales coal workers from the 1930s. The principal directions of enquiry remained the same as in Scotland a century before, namely the components of coal mine dust responsible for fibrosis and the additional factor required for the development of massive fibrosis. The combined human and experimental evidence now makes possible conclusions in which confidence may be placed.

Coal Mining↗
PubMed1991

Minerals, fibrosis, and the lung.

Determinants of pulmonary fibrosis induced by inhaled mineral dusts include quantity retained, particle size, and surface area, together with their physical form and the reactive surface groups presented to alveolar cells. The outstanding problem is to ascertain how these factors exert their deleterious effects. Both compact and fibrous minerals inflict membrane damage, for which chemical mechanisms still leave uncertainty. A major weakness of cytotoxicity studies, even when lipid peroxidation and reactive oxygen species are considered, lies in tacitly assuming that membrane damage suffices to account for fibrogenesis, whereas the parallel occurrence of such manifestations does not necessarily imply causation. The two-phase procedure established that particles, both compact and fibrous, induce release of a macrophage factor that provokes fibroblasts into collagen synthesis. The amino acid composition of the macrophage fibrogenic factor was characterized and its intracellular action explained. Fibrous particles introduce complexities respecting type, durability, and dimensions. Asbestotic fibrosis is believed to depend on long fibers, but scrutiny of the evidence from experimental and human sources reveals that a role for short fibers needs to be entertained. Using the two-phase system, short fibers proved fibrogenic. Other mechanisms, agonistic and antagonistic, may participate. Growth factors may affect the fibroblast population and collagen production, with cytokines such as interleukin-1 and tumor necrosis factor exerting control. Immune involvement is best regarded as an epiphenomenon. Downregulation of fibrogenesis may follow collagenase release from macrophages and fibroblasts, while augmented type II cell secretion of lipid can interfere with the macrophage-particle reaction.

Animals↗
PubMed1989

Relationship of lipid secretion and particle size to diffuse interstitial change in pneumoconiosis: a pathogenetic perspective.

Simple pneumoconiosis due to compact particles, notably in coal workers, sometimes departs from its customary focal formations and a more diffuse distribution of dust-impregnated fibrosis is superimposed. To account for this change, which may be reflected in the acquisition of radiologically irregular opacities in addition to rounded ones, attention is directed first toward type II alveolar epithelium. These cells come early into contact with inhaled particles and the lipid secretion provoked prevents their characteristic aggregation, so they remain in a more dispersed state and the consequent fibrotic reaction then tends to become diffuse. Second, submicron particles appear to act not from within the alveolus like the more usual larger ones, but after direct passage through type I epithelium into the interstitium, where lacking focal accumulation they are able to produce diffuse changes. Complexities, however, remain, among which are coalescence of focal lesions as their severity increases and interplay of agents producing interstitial fibrosis in the general population.

Animals↗
PubMed1988

Prevalence and pathogenesis of pneumoconiosis in coal workers.

Dust dose and composition do not appear to account wholly for changes in the prevalence of coal workers' pneumoconiosis in Europe. In certain coal pits high progression evidently occurred with relatively low dust exposure or vice versa, whereas progression in relation to dust levels might be variable. Exceptionally high quartz concentrations occur in coal mine dust when pneumoconiosis may progress with unusual rapidity. Under such circumstances lesions resembling silicotic nodules may be found, but with the customarily lower levels of quartz the pathological features assume the form characteristic of coal workers. Morphological changes in relation to dust content of human and animal lungs, as well as cellular behavior, have not accounted completely for the epidemiological findings. Considering all the pathological evidence helps explain the pathogenesis of pneumoconiosis and vagaries of progression. The origin of progressive massive fibrosis cannot be explained simply in terms of dust burden or immunological features, and the role of an infective factor cannot be dismissed. Moreover, lipid secretion by alveolar epithelium introduces a new element that could affect the development of simple and complicated pneumoconiosis. In vitro, cytotoxicity appeared to be too variable for predictive purposes, though direct assay of fibrogenicity using the macrophage fibrogenic factor suggested that dust dose was more important than dust composition. Assessing individual susceptibility presents serious obstacles.

Coal Mining↗
PubMed1986

Determinants of pulmonary fibrosis and lipidosis in the silica model.

The conditions which might favour development of the fibrotic or the lipid component of the pulmonary reaction to inhaled quartz were examined in rats. Smaller particle size and freedom from surface contamination by amorphous silica or iron oxide, status of the animals whether specific pathogen-free or conventional, and the resistance of cell membranes to damage appeared to bear on fibrogenesis. Increased membrane stability by treatment with polyvinylpyridine-N-oxide abolished not only the fibrosis but also the response of type II cells and hence lipidosis. The rate and intensity of quartz deposition may also affect the response, a low concentration inhaled over a long period favouring nodulation. No other manipulations, environmental or pharmacological, succeeded in inhibiting lipidosis to the benefit of fibrosis. Guinea pigs, however, behaved differently, their reaction being characterized by massive alveolar accumulation of dust-bearing macrophages and type II cell hyperplasia but not by lipidosis. The species variation is unexplained but macrophage predominance may represent a phase that later transforms to lipidosis. The experimental findings may have implications for forms of pneumoconiosis other than silicosis.

Animals↗
PubMed1985

Silica, pneumoconiosis, and carcinoma of the lung.

The current argument about the carcinogenicity of inhaled silica is not clarified by reliance on morbidity and mortality experience divorced from or incompletely related to data on environmental exposure. Human evidence provides the ultimate basis for assessing such risks, and numerous studies of the effects of inhaling dusts rich or poor in silica content on the prevalence of pulmonary carcinoma have been performed on large series of cases from major mining areas of the world. When due allowance is made for substances inhaled concomitantly with exposure to silica and for personal pollution by cigarette smoking, the weight of evidence is against a carcinogenic role for uncombined silicon dioxide. Moreover, pneumoconiosis due to compact mineral particles does not appear to determine the onset of lung cancer. Cellular behaviour suggests reasons for the different responses to compact and fibrous particles acting alone.

Coal Mining↗
PubMed1985

Population and ultrastructural changes in murine alveolar cells following 239PuO2 inhalation.

Early changes affecting the principal cellular components of pulmonary alveoli after inhaling 239plutonium dioxide were followed by quantitative and qualitative electron microscopy in mice and rats. Different accumulated doses of a irradiation were achieved. The numbers of alveolar macrophages and interstitial mononuclear cells rose in mice especially after a higher dose of radiation, whilst in rats interstitial fibroblasts were increased. The evidence from mice suggested pronounced secretory activity of type II epithelial cells with subsequent uptake of phospholipid by alveolar macrophages, which developed large cytoplasmic inclusions, but rats were much less severely affected. Pneumonitis was not a feature and with the dosage of radiation employed endothelium escaped structural damage. Sensitivity between species differed, both according to cell type and to intensity of exposure, so demanding caution in the application of experimental findings to man.

Animals↗
PubMed1979

Replenishment of alveolar macrophages in silicosis: implication of recruitment by lipid feed-back.

The deposition of quartz in the pulmonary alveoli creates a major demand for macrophages to replace those destroyed, but local proliferation of monocytes appeared to be minimal and the role of systemic recruitment was therefore explored. Injected silica and lipids stimulated the phagocytic function of the mononuclear phagocytic system (MPS), whilst inhaled silica provoked lipid accumulation in the lung, thus suggesting that lipid might also induce a proliferative response in the marrow. Using marrow cultures, cells of the rat MPS were identified by size and phagocytic capacity for latex microspheres, and then subjected to kinetic analysis in litter-mate pairs by single and double labelling autoradiography, under normal conditions and after administration of lipid extracted from rat lungs consolidated by silica-induced alveolar lipo-proteinosis. Treatment of the results by a new device facilitated distinction of promonocytes from monocytes and thus afforded a more precise means of assessing MPS kinetics. The duration of DNA synthesis and the cell-cycle time of promonocytes were reduced and the rate of entry into DNA synthesis increased as a result of i.v. injection of lung lipid. These findings support the involvement of systemic recruitment of monocytes from the marrow by a positive feed-back mechanism when a powerful irritant persists in the lungs and the results are discussed in the overall context of silicotic fibrogenesis.

Animals↗
PubMed1977

Cell kinetics of urethane-induced murine pulmonary adenomas: III. Implications of the disparity between the rates of entry into DNA synthesis and into mitosis.

Metaphase arrest by vincristine in urethane-induced murine pulmonary adenomas became linear after an interval of 60 min. The rate of entry into metaphase was 0-191%/h, which was considerably less than the 1%/h for the rate of entry into DNA synthesis obtained previously by double labelling. The duration of prophase plus metaphase was calculated to be 1-7 h. A growth fraction of 9% and a cell-loss factor of 52% were derived. The disparity between rates of entry into DNA synthesis and into metaphase was investigated by microdensitometry on Feulgen-stained squash preparations of tumours of varying ages. Tne DNA profiles showed an increasing frequency of hyperdiploid nuclei with age. Circumstantial evidence for polyploidy was provided by the presence of many binucleate cells in the tumours. By analogy with the liver, these cells may well represent a stage in the development of polyploidy, and the possible relevance of these findings to the neoplastic process is considered.

Adenoma↗
PubMed1977

Effect of inhaled plutonium dioxide on development of urethan-induced pulmonary adenomas.

Mice were exposed to plutonium dioxide (PuO2) aerosols 2 weeks before or after urethan injection. Both exposures reduced the number and size of adenomas. The incidence of arrested metaphases showed no consistently significant differences between plutonium-exposed and mock-exposed animals. The results are discussed in relation to recent electron microscopic evidence of degenerative changes in the type II epithelial cells of the mouse lung following PuO2 inhalation. It is concluded that damage at the cellular level may account for the observed reduction in growth of pulmonary adenomas in mice whose lungs contained plutonium particles.

Adenoma↗
PubMed1976

Cell kinetics of urethane-induced murine pulmonary adenomata: II, the growth fraction and cell loss factor.

Continuous labelling of urethane induced pulmonary adenomata in adult male A2G mice at intervals up to 20 weeks showed that the growth fraction fell progressively from 18% at 7 weeks to 7% at 20 weeks. This fall appears to be wholly responsible for the decrease in production of adenoma cells with age. A fraction labelled mitoses curve was constructed for pulmonary adenomata at 14 weeks post urethane. Only the first peak was apparent, giving median t2 and ts values of 2 and 9 h respectively. The cell cycle time was calculated at 45 h and the growth fraction at 6-2%, whilst the cell loss factor was estimated at 31%. Other cell loss values were calculated from data on the rate of entry into DNA synthesis obtained previously by double labelling. These values remained constant with time at 83-95%, suggesting that cell loss is in some way linked to cell production. However, the development of polyploidy in adenoma cells could not be eliminated. No areas of necrosis were seen in the adenomata at any time although karyorrhexis occurred in isolated cells. The labelling characteristics of alveolar wall cells in the same lung sections as the adenomata did not vary with time and the continuous labelling curve gave a growth fraction of 1-8%, a DNA synthetic time of 10 h and a cell cycle time of 30 h.

Adenoma↗
PubMed1975

Cell kinetics of urethane induced murine pulmonary adenomata: I. The growth rate.

A single injection of urethane into adult male A2G mice produced an increase in the proliferative rate of alveolar wall cells, reaching a peak at 2 weeks post urethan (PU) and declining to control levels by 2 months PU. During this urethane induced proliferative response the single and double labelling indices and the native metaphase index were all elevated although there was no corresponding alteration in the arrested metaphase index. This proliferative response may not be restricted to hyperplasia of potentially neoplastic cells, such as type II epithelium, but may also include type I epithelial cells and alveolar macrophage precursors. However, it was impossible to identify individual cell populations by methods used. The growth rate of adenomata decrease with time and cell kinetic techniques showed that the rates of entry of adenoma cells into DNA synthesis and into metaphase were decreasing concurrently with the growth rate. Thus the rate of cell production falls as adenomata age but how much cell loss contributes to the decrease in growth rate is not yet known. Decreasing cell production could be due to an increased cell cycle time and/or a decreased growth fraction. The duration of DNA synthesis in adenomata increased markedly as the mice survived, suggesting that the cell cycle time might be increased, but further experiments are required to determine whether the growth fraction changes. Attention is drawn to a complication that Colcemid introduces into kinetic studies on alveolar wall cells.

Adenoma↗