Early lung events following low-dose asbestos exposure.
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Animals↗
Biomedical subjects
R Bégin
Publications and source records attributed to R Bégin.
Sequential analysis of the bronchoalveolar milieu in conscious sheep.
A conscious sheep model was developed to study sequentially the alveolar milieu by respiratory physiological measurements, transbronchial lung biopsy, and bronchoalveolar lavage. The former included all lung volumes, respiratory mechanics, and gas exchange measurements. For all these measurements, intraindividual variations were similar to those reported in humans or anesthetized primates. They were not significantly altered by the repetition of each procedure of the study. Transbronchial lung biopsy specimens were adequate in 80% of cases and yielded 100 alveoli and more in 75% of specimens (mean alveolar count = 690; bronchioles = 4.1; vessels = 3.2). Bronchoalveolar lavage (BAL) yielded a 60% effluent and a mean of over 9 X 10(6) cells in each of the three sets of measurements. BAL was found to induce a mild transient hypoxemia that was completely resolved within 2 h. Cellular and biochemical analyses of BAL effluent in the three series done at 2-wk intervals did not change significantly. It is concluded that the procedures repeated on the conscious sheep model at 2-wk intervals do not influence the respiratory physiological measurements, lung histopathology, or the BAL analyses.
Animals↗
Significant increases of cyclic AMP and alkaline phosphatase in bronchoalveolar lavage fluids of sheep exposed to asbestos.
Exposure to asbestos for six months caused a significant increase of adenosine 3',5'-cyclic monophosphate (cAMP) levels (2-fold in bronchoalveolar lavage (BAL) fluids of sheep with no significant change in guanosine 3',5'-cyclic monophosphate (cGMP) and alkaline phosphatase (AP) activity. When exposure was prolonged for another 3 month-period, the increase in cAMP levels persisted and was accompanied by a 4-fold stimulation of AP activity, and enzyme associated with the surfactant fraction of BAL fluids.
Alkaline Phosphatase↗
The adaptation of neonatal blood to metabolic acidosis and its effect on cisternal oxygen tension.
In eight newborn lambs, the adaption of blood to acidosis was studied by sequential measurements of P50 in vitro (pH 7.4; 37 degrees C) and P50 in vivo (animal's pH and temperature, 39 degrees C) during the course of HCl-induced metabolic acidosis. The benefit of the change in both P50 on tissue oxygen tension was studied by the change in O2 partial pressure at the level of the cisterna magna. Eight hr of acidosis caused a significant (P less than 0.01) decrease in P50 in vitro which fell from 29.0 to 24.4 torr. Nonetheless, because of pH effect on the hemoglobin affinity, the corresponding P50 in vivo was increased from 32.4 to 36.3 torr. This latter rise in the in vivo O2 affinity contributed to increase (P less than 0.01) the cisternal O2 tension. It is concluded that the hemoglobin of the newborn is capable of adaption to metabolic acidosis by displacing the in vivo O2 dissociation curve to the right favouring a greater unloading of O2 at the tissue level and thus preventing tissue hypoxia during metabolic acidosis.
Acidosis↗
Neural drive and ventilatory strategy of breathing in normal children, and in patients with cystic fibrosis and asthma.
The drive and performance of breathing during hypercapnia, isocapnic hypoxia, and transient hyperoxia were studied in 20 normal children (mean age 12.3 years), in ten children with asthma, and in ten children with cystic fibrosis (CF) matched by sex and age. These latter two groups of patients had had obstructive respiratory symptoms since infancy and their pulmonary disease was of moderate severity as documented by their pulmonary function studies. During hypercapnia, normal children had a linear increase in minute ventilation (delta VE), in tidal volume (delta VT) and in the inspiratory drive (VT/Ti). The drive of breathing was evaluated by the occlusion pressure (P0.1) at functional residual capacity. The P0.1 response to PaCO2 was linear. Patients with asthma and CF showed a blunted ventilatory response (delta VE, delta VT, VT/Ti) to Co2 but a normal response in P0.1. In normal subjects, the test of isocarbic hypoxia demonstrated an exponential type of increase in delta VE, delta VT, and P0.1 as PAO2 decreased from 110 to 40 torr. With severe hypoxia (PAO2 less than 50 torr), children with CF (but not asthmatic patients) experienced a paradoxical decrease in delta VE while the drive (P0.1) remained above normal in both groups of patients. Finally, the transient O2 inhalation test caused a decrease in VE of 26%, 21%, an 34%, respectively, in normal subjects, in asthmatic children, and in children with CF. It is concluded that the CO2 and O2 drive of normal children resembles that described for adults and that the CO2 and O2 command of breathing is normal in children with asthma and CF. However, the ventilatory response in children with chronic obstructive pulmonary disease is subnormal probably due to the impairment of the respiratory mechanics. Finally the respiratory depression induced by severe hypoxia in children with CF is unexplained, but it may reflect the high dependency of their respiratory muscle on oxygen supply.
Adolescent↗
Early effects of low-doses exposure to asbestos on local cellular immune responses in the lung.
We recently developed an animal model to study the pulmonary reactions after exposure to environmental pollutants. In this model, sheep received monthly intratracheal instillations of a suspension of varying amounts of chrysotile asbestos in saline. All animals were studied by pulmonary function tests, transbronchial biopsies, and bronchoalveolar lavage. During the 6 mo of the study, no changes were seen in the 2 former tests, but bronchoalveolar lavage yielded leukocytes that responded with enhanced proliferative activity to concanavalin A, pokeweed mitogen, and staphylococcal lysate. The response to phytohemagglutinin was poor but also enhanced in the asbestos-exposed animals. Enhanced responsiveness was dose-related, except for the highest dose used, 128 mg, which was associated with a less enhanced proliferative response or none. Our data suggest that the initial response to low-dose exposure to asbestos consists in a stimulation of lymphocyte function; the possibility that this phenomenon may be linked to the eventual fibrogenic response of asbestosis warrants further studies.
Animals↗
Control of breathing in Duchenne's muscular dystrophy.
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Adolescent↗
Phospholipase A activity and prostaglandin release from alveolar macrophages exposed to asbestos.
The effect of asbestos (canadian chrysotile B) was studied on macrophages harvested by guinea-pig bronchoalveolar lavage. In short term incubation (3 hrs), asbestos (1 mg) induced a highly significant increase in macrophage phospholipase A activity and prostaglandin synthesis. At lower concentrations of the fibers (10 micrograms and 100 micrograms), no significant change of macrophage activity was noted following our incubation period. The modification by asbestos of membrane integrity and functions is suggested.
Animals↗
Cerebral hypoxia from bicarbonate infusion in diabetic acidosis.
To study the delivery of oxygen to the cerebral tissue during metabolic acidosis and its therapy with bicarbonate (NaHCO3), oxygen partial pressure of the cisternal fluid was measured in 12 experiments of HCl-induced acidemia and eight experiments of diabetic ketoacidosis in 16 unanesthetized dogs. Full correction of acidosis with bicarbonate caused a significant (P less than 0.05) decrease in Pcsf 2: in the HCl acidotic dogs, Pcsfo2 decreased from 53.9 +/- 2.2 torr to 45.9 +/- 2.3 torr within one hour; in the ketoacidotic dogs, Pcsfo2 decreased for 48.5 +/- 5.4 torr to 26.7 +/- 6.6 torr within six hours. In the ketoacidotic dogs not treated with bicarbonate, there was no significant change in Pcsfo2. An inverse relationship (P less than 0.01) between the cisternal lactic acid level and the cisternal PO2 was also observed. It is concluded that NaHCO3 therapy in diabetic ketoacidosis decreases the cerebral O2 availability and that cerebral hypoxia contributes to the brain dysfunction encountered after the initiation of such therapy in acidemia.
Acidosis↗
Control and modulation of respiration in Steinert's myotonic dystrophy.
Respiratory impairment in patients with Steinert's muscular dystrophy is known to lead to respiratory failure. Both the blunted chemical drive of breathing and the respiratory muscle weakness have been cited in the pathophysiology of premature death in these patients. To further assess the chemical control of breathing in these patients, we measured their respiratory responses to hypoxia (Weil's method), hyperoxia (Dejours' method), and hypercapnia (Read's method). In response to the stimuli from these respiratory centers, minute ventilation (VE), tidal volume (VT), respiratory frequency (F), mean inspiratory flow rate (VT/Ti), and occlusion pressure (P0.1) were measured in 12 patients and in 12 normal persons matched to the patients on the basis of age, sex, and arm span. The patients were similar to the control subjects in occlusion pressure results. However, they differed significantly (P less than 0.01) in ventilatory responses by a lower VE, lower VT, higher F, and lower VT/Ti in response to the hypercapnia and hypoxia tests. The responses of patients and control subjects were similar during the hyperoxia tests. Our study, therefore, established that the chemosensitivity of the respiratory centers, as measured by P0.1, is well preserved in Steinert's myotonic dystrophy, but the output to breathing (VE, VT, F, VT/Ti) is modulated by the impaired respiratory mechanics causing a tachypneic breathing pattern, even in the absence of restricted lung volume.
Adolescent↗
[The fetus, an involuntary smoker: a study of carbon monoxide in pregnant women and their newborn infants].
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Adult↗
Central chemical regulation of respiration in term newborn.
The role of the medullary H+-sensitive chemoreceptors on the drive of breathing was studied in 10 unanesthetized newborn animals (8 lambs and 2 kids). The experiment consisted of sequential measurements of ventilation (VE) during a progressive change in the arterial pH (pHa) and in the pH of the cisternal cerebrospinal fluid (pHCSF), induced by intravenous infusion of hydrochloric acid (HCl) followed after an 8-h steady state of acidosis by rapid bicarbonate [HCO3-] infusion. It is shown that a rapid change in [HCO3-]CSF occurs during the infusion of HCl or NaHCO3. As a consequence both CSF and arterial pH change in the the same direction and large changes in pHCSF (from 7.331 to 7.227) were observed. Such CSF acidosis did not contribute to further increase VE beyond the level by hyperventilation induced by the initial fall of pHa. The ventilatory response to the decrease in pHa was found to fall off with moderate to severe acidosis (pHa less than 7.20). In conclusion, this study demonstrates an instability of the pHCSF during neonatal metabolic acidosis and it suggests an immaturity of both the H+-sensitive medullary and peripheral chemoreceptors in the 8-day-old newborns.
Acidosis↗
[Pulmonary atelectasis caused by bronchocentric aspergillosis: an other farmer's pneumoconiosis].
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Agricultural Workers' Diseases↗
Dysplasias of uterine cervix: epidemiological aspects: role of age at first coitus and use of oral contraceptives.
Age at first coitus and use of oral contraceptives were studied in a highly homogeneous population (French Canadian) during a cytologic cervical cancer screening program. Both factors were known in 84,540 women without cervical lesions and in 2017 patients with mild and moderate dysplasia. Highly significant correlations were found between: early onset of sexual activity and occurrence of dysplasia; oral contraceptive use and occurrence of dysplasia; early age at first coitus and oral contraceptive use. When correlated for age at first coitus, there was a significant excess of dysplasias in oral contraceptive users. Dysplasia of the uterine cervix behaves epidemiologically like carcinoma in situ and invasive squamous carcinoma, that is, essentially as a venereal disease. It remains to be seen whether all dysplasias form one continuum or whether there are two morphologically similar but biologically distinct forms of dysplasia: one more frequent, regressing spontaneously, the other relatively rare, progressing to carcinoma in situ and invasive squamous carcinoma of the cervix.
Adolescent↗
Mineralogy of lung tissue in dental laboratory technicians' pneumoconiosis.
This article reports on a case of pneumoconiosis in a dental laboratory technician with a history of respiratory exposure to dental materials. Special attention is paid to the mineralogical analysis of the lung biopsy. The abundance of chromium, cobalt, and silica particles suggests that the dental technician's pneumoconiosis is the result of the combined effects of hard metal dusts and silica particles generated during finishing dental frameworks. Adequate technical protection such as a local ventilation system should be considered in dental laboratories to prevent respiratory exposure of dental technicians to airborne contaminants.
Chromium↗
Influence of continued asbestos exposure on the outcome of asbestosis in sheep.
Clinical recognition of asbestosis is generally followed by exclusion of the worker from the active workforce and appropriate compensation. Given the better industrial hygiene conditions of the 1990s, and a recent report suggesting that low-level asbestos exposure may not affect progression of asbestosis, the medical rationale to pension asbestos workers with early asbestosis has been questioned in the legal courts. To study the influence of asbestos exposure after established asbestosis, we enrolled 25 sheep. Ten were normal controls (group A) and 15 had asbestosis, after 2 years of repeated 10-day interval, 100-mg chrysotile exposure (Eur Respir J 3:81-90, 1990). The asbestotic sheep were divided into a group of five without further asbestos exposure (group B), a group of five with continued exposure at induction doses (group C), and a group of five with continued exposure of 10% induction doses (group D). All were followed by chest radiography, lung function, and lung lavage at 3-month intervals and histopathology when appropriate. During the 12-month study, mortality occurred only in groups C and D (40% in both, P less than .02). Chest radiograph and lung function were worse in groups C and D. The enhanced macrophagic and neutrophilic alveolitis observed on lung lavage and the pathological findings in the deceased sheep suggested progression of asbestosis and bacterial infections as the major contributors to the higher mortality of sheep in groups C and D. In conclusion, asbestos exposure after disease recognition was associated with increased mortality in our sheep and this was largely associated with progression of asbestosis and added lung infection.
Animals↗
Silica exposure induces cytotoxicity and proliferative activity of type II pneumocytes.
The contribution of the type II pneumocyte to the pathogenesis of silicosis is largely unknown. Prominent features of silicosis are hyperplasia and hypertrophy of type II epithelial cells, often accompanied by phospholipid accumulation in the lung. The biologic regulation of these events is poorly understood. This study addresses the question of a direct effect of silica on type II pneumocytes, since direct contact of the inhaled silica dust can occur in vivo. Type II cells were isolated from fetal rat lungs and their epithelial specificity was verified. Experiments were performed on 2nd passage monolayers in 2% serum. Repair, replication, and growth activity was evaluated by the incorporation of [3H]thymidine. Cytotoxicity was measured by quantitating the release of [14C]adenine and expressed as a cytotoxicity index (CI). Type II cell proliferation and cytotoxicity were evaluated for the mineral dusts silica (SiO2), aluminum-treated silica (SiO2AlK), and titanium (TiO2). Of these mineral dusts, only low concentrations of silica increased type II cell [3H]thymidine incorporation (silica 2.5 micrograms/mL: 52% above control, P less than .05; silica 20 micrograms/mL: 57% above control, P less than .02). In addition, silica increased the cell number significantly, although to a lesser degree. Exposure of the type II epithelial cells to silica dust for 24 h resulted in dose-dependent cytotoxicity (silica 10 micrograms/mL, CI = 9.1%, P less than .0002; 250 micrograms/mL, CI = 45.1%, P less than .0001). SiO2Al completely suppressed these proliferation and cytotoxicity effects, which were then similar to those of the inert dust, TiO2. These data suggest that direct exposure and contact of the type II pneumocytes to low-dose silica dust initiated repair, replication, and growth activity, while exposure to higher silica concentrations resulted in marked cytotoxicity. Both the repair, replication, and growth and the cytotoxic responses of the type II epithelial cells to silica exposure are related to the surface properties of silica.
Animals↗
Silica-exposed lung fluids have a proliferative activity for type II epithelial cells: a study on human and sheep alveolar fluids.
The type II pneumocyte changes in silicosis are characterized by hyperplasic and hypertrophic epithelial cells, and increased surfactant phospholipids in the bronchoalveolar lavage fluids (BALF). To assess the proliferative activity of alveolar lining fluids, BALF were applied on type II cell cultures. The growth-promoting activity was studied by tritiated thymidine incorporation for 24 h, and the cell number was measured by an electronic counting after a 48-h exposure time. Human BALF from 3 subsets of workers exposed to silica, staged according to ILO classification (silica exposed-workers without disease: hSWD n = 6; workers with simple silicosis: hSS n = 7; workers with confluent silicosis: hCS n = 5), were compared to healthy volunteers (hC n = 6). Sheep BALF from our model of silicosis and control animals (sS and sC) were studied at months 0, 6, and 24 of exposure. A clear enhancement was found in type II cell DNA synthesis under the effect of either normal and silicotic human or sheep BALF, in comparison to the negative control (p less than .05). In addition hSWD and hSS BALF as sS BALF at 20% dilution (peak activity) were significantly more stimulating than the normal alveolar fluids from the same species (p less than .05). The highest sheep BALF stimulatory activity was found at month 6 (170% of increase vs control, p less than .05) and clearly correlated with the high cellularity of BALF. The thymidine incorporation was supported by changes in cell counts. Sheep silicotic BALF run through G50 columns identified at least 3 molecular weight (MW) areas of mitogenic activity between 30 and 5 kDa. Biochemical characteristics of growth factors in the above MW range (PDGF, FGF, TGF alpha, EGF) were tested. Increased mitogenic activity of type II cells eluted from heparin sepharose columns loaded with silicotic sheep BALF, at 0.5 and 1 M NaCl, corresponded to the removal areas of PDGF- and acidic FGF-like heparin-binding molecules. The high proliferative activity on type II cells of the latter two molecules, alone or in combination with other growth factors, was demonstrated in vitro (greater than 9 x control). In conclusion, a stimulatory activity for type II cell growth was found in the normal human and sheep alveolar lining fluid. This activity was clearly enhanced in the early stages of human and sheep silicosis. The BALF type II cell growth factors had biochemical characteristics consistent with the PDGF- and FGF-like molecules.
Animals↗