The hot air on passive smoking. Experts who evaluated studies seem not to have had relevant experience.
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Humans↗
Biomedical subjects
B Nemery
Publications and source records attributed to B Nemery.
Dermal and respiratory sensitization to chromate in a cement floorer.
BACKGROUND: To report a well-documented case of both allergic contact dermatitis and occupational asthma due to chromate exposure in a 48-year-old floorer. METHODS AND RESULTS: A 48-year-old floorer, occupationally exposed to cement and with a documented chromate contact dermatitis, reported dyspnea and wheezing after work. These conditions were demonstrated by self-measured sequential peak expiratory flows. A first bronchial provocation (BPT) with potassium dichromate (K2Cr2O7) (0.3% nebulized for a total of 60 minutes) led to pronounced and sustained decreases in forced expiratory volume in 1 second (FEV1) and forced vital capacity, accompanied by pruritus, a decrease in arterial PO2, a slight rise in temperature, and peripheral blood leukocytosis. (This concentration of K2Cr2O7 is not recommended for BPT). Bronchoalveolar lavage performed 2 days later showed 18% eosinophils. Tow years later, a BPT with a lower dose of K2Cr2O7 (0.01% for the total of 31 min) led to an "earl late" reaction (FEV1 dropped by 195 compared with the initial FEV1 value), accompanied by pruritus. A BPT with dry cement, containing 12 ppm hexavalent chromium, was borderline (FEV1 dropped by 13%), and a similar result (FEV1 dropped by 14%) was obtained after smoking five cigarettes, laced with 10 mg of cement per cigarette. CONCLUSIONS: This report illustrates that a subject, with allergic contact dermatitis to chromates, may develop a respiratory allergic reaction to an airborne source of this metal. The main novelty of our report is that the smoking of cigarettes contaminated with cement may have been significant factor in the causation or elicitation of these reactions.
Asthma↗
Protective effects of the lazaroid U-74389G against hyperoxia in rat type II pneumocytes.
The aims of this study were to investigate the effect of hyperoxia on O2(-.), H2O2 and .NO generation and iNOS mRNA levels in rat type II pneumocytes in vitro and the possible protective effect of the lazaroid U-74389G. Rat type II pneumocytes were exposed, 36 h after isolation, to air, 60% or 85% O2 for 48 h. At the beginning of the experiment and 24 h later, the cells were exposed for 30 min to either 30 microM U-74389G or only the vehicle for the lazaroid (control). Exposure to 60% and 85% O2 decreased nitrite production 2.9-fold and 3.9-fold, and increased O2(-.) and H2O2 generation 4.6-fold and 6.7-fold, respectively. In the 85% O2-exposed cells, hyperoxia increased lipid peroxidation (thiobarbituric acid reactive substances, TBARS production) 2-fold and iNOS mRNA production 5.4-fold. U-74389G prevented the decrease in nitrite and the rise in O2(-.) and H2O2 production, the increase in TBARS and the rise in iNOS mRNA after hyperoxia. We conclude that exposure of type II pneumocytes in vitro to subtoxic oxygen levels leads to a disturbance in the .NO-O2(-.) balance despite increased iNOS mRNA levels. The lazaroid U-74389G appears to be a useful compound in the protection of hyperoxic lung injury by restoration of this .NO-O2(-.) balance and prevention of TBARS formation.
Animals↗
A novel cause for bronchiolitis obliterans organizing pneumonia: exposure to paint aerosols in textile workshops.
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Adipates↗
Interstitial lung disease more than 40 years after a 5 year occupational exposure to talc.
A 62 yr old woman was initially diagnosed with sarcoidosis until a thoracoscopic biopsy revealed the presence of numerous birefringent particles in fibrotic areas of the centrilobular lung zones. These particles were examined by electron microscopy and X-ray spectrometry and characterized as impure talc. Further inquiry into her occupational history revealed that she had worked from the age of 14-18 yrs in a factory making rubber hoses, where she had had an intense exposure to talc. There was no evidence of silicosis or asbestosis, and other significant causes of interstitial lung disease were excluded. This case emphasizes the importance of a thorough occupational history, which may reveal a remote and forgotten exposure to a significant cause of interstitial lung disease. Although this presentation of talcosis is unusual, this case suggests that even a relatively short, but presumably intense exposure to talc more than 40 yrs previously may be a cause of progressive lung fibrosis.
Female↗
Assessment of the sensitization potential of five metal salts in the murine local lymph node assay.
The murine local lymph node assay (LLNA) has been proposed as a predictive test for the identification of sensitizing agents. We used this test to compare the sensitization potential of NiSO4, K2Cr2O7, CoCl2, Na2PtCl6 and BeSO4, salts of metals which have all been associated with allergic contact dermatitis and either bronchial asthma orinterstitial lung disease, by either humoral or cell-mediated allergic mechanisms. BALB/c mice (n = 3 per concentration studied, three concentrations studied per metal) received three daily applications of the metal salt (in DMSO) on the dorsum of both ears. On the fourth day the draining auricular lymph nodes were removed and the incorporation of [3H]-thymidine in the lymphocytes in culture was compared to that of concurrent vehicle-treated control mice, thus enabling to derive a stimulation index (SI), indicative of immunological sensitization potential. Each experiment was performed three times. Oxazolone and toluene diisocyanate, chosen as positive controls, yielded strongly positive SI values (> 20 and > 30 respectively). Na2PtCl6 (SI 2.6 +/- 1.0 at 2.5%), CoCl2 (SI 2.8 +/- 0.5 at 5%) and possibly also K2Cr2O7 (SI 2.1 +/- 1.2 at 0.5%) were positive in the LLNA, whereas NiSO4 (SI 0.9 +/- 0.2 at 5%) and BeSO4 (SI 1.3 +/- 0.6 at 4%) were negative. Although our results are still limited by the fact that only one mice strain was tested, they indicate that there is no strict relationship between the sensitization potential of metal salts, as evaluated in the murine LLNA, and their potential to cause either respiratory or dermal allergic disease. Consequently, caution should be exercised before proposing the murine LLNA as a valid test to predict the sensitization potential of low molecular weight chemicals.
Allergens↗
Nocturnal oxygen desaturation, as assessed by home oximetry, in long-term solvent-exposed workers.
Recent studies have suggested that occupational exposure to solvents may be a cause of sleep apnea. Digital oximetry during one night was performed in solvent-exposed offset printers (n = 21) and in a control group (n = 21), using a Palco 400 Pulse Oximeter. The threshold for recording was set at an arterial oxygen saturation (SaO2) of 90%. Furthermore, computerized neurobehavioral tests (NES) and a solvent-related complaints questionnaire (NSC-60) were administered. The mean exposure time was 15 years (SD = 10). Hygiene measurements revealed a large number of different solvents and a cumulative exposure between 15% and 97% of the "cumulative TLV." The exposed workers had more solvent-related complaints, especially regarding mood (analysis of covariance, P = 0.02), than the nonexposed workers. The neurobehavioral tests indicated that hand-eye coordination was significantly worse in the exposed group (analysis of covariance, P = 0.03). The frequency of nocturnal desaturation was significantly higher in the printers (1.7 events/hr +/- SD = 1.5) than in the controls (0.6 events/hr +/- SD = 1.3) (Mann-Whitney test, P < 0.01). Also, the duration of desaturation was longer in the exposed workers: 3.2 min/hr (SD = 3.2) vs 1.2 min/hr (SD = 2.3) (Mann-Whitney test, P < 0.01). In the analysis of covariance, exposure (P = 0.04) and the interaction between smoking and exposure (P = 0.02) were shown to contribute significantly to the excess of nocturnal desaturation in the exposed. The same was true for the mean duration of desaturation (exposure: P = 0.02 and interaction exposure smoking: P = 0.02). The significant interaction was due to a more pronounced effect of solvent exposure among the nonsmoker group. No relation was found between the excess of complaints or the neuroperformance effects and the oximetry data. These data reinforce the presumption that occupational solvent exposure might contribute to sleep-disordered breathing.
Adult↗
Susceptibility to hard metal lung disease is strongly associated with the presence of glutamate 69 in HLA-DP beta chain.
Clinical, epidemiological and experimental data indicate that inhaled metal dust containing cobalt may produce an interstitial lung disease termed "hard metal disease" (HMD). Some aspects of this pathology such as the lack of correlation with dose exposure, the low frequency of the disease and the presence of T cells in the inflammation site, all suggest the existence of a genetic susceptibility, possibly to an immunological response to cobalt or to self proteins modified by cobalt. Here we report that HMD is strongly associated with residue Glu-69 of the HLA-DP beta chain. All patients, except for one with a rare genotype, possessed this marker as compared to 17 out of 35 exposed unaffected individuals (p = 0.0014). These data allow us to genetically distinguish a subgroup of cobalt-exposed individuals at risk for HMD, independently from the more common allergic reaction.
Adult↗
Increase in gamma-glutamyltransferase by glutathione depletion in rat type II pneumocytes.
The purpose of our study was to investigate the effect of oxidative stress or intracellular glutathione (GSH) depletion on gamma-glutamyltransferase (gamma-GT) activity in cultured type II pneumocytes. Twenty-four hours after isolation, primary cultures of rat type II pneumocytes were preincubated with one of four compounds: 15, 30, 60, 125, 250 microM L-buthionine-[SR]-sulfoximine (BSO) for 3 h; 100, 200, 400, 800 microM tertiary-butylhydroperoxide (t-BOOH) for 45 min; 10, 25, 50, 100 microM menadione for 15 min; 100, 1000 microM paraquat for 1 h. GSH levels, H2O2 and O2.- generation were measured immediately after the incubation, gamma-GT activity and GSH levels also up to 24 h or 48 h later. Exposure to BSO led to a persistent GSH depletion without increase in H2O2 or O2.- production, together with a dose and time-dependent increase (doubling) of gamma-GT activity with a nonsignificant increase in gamma-GT mRNA expression 24 h after exposure to BSO. Exposure to 100 microM menadione, which increased H2O2 production, decreased gamma-GT activity. t-BOOH or paraquat did not give rise to a measurable increase in H2O2 or O2.-. Paraquat did not affect initial GSH levels, but increased GSH and decreased gamma-GT activity 24 h later. t-BOOH (400 and 800 microM) initially decreased GSH, and tended to increase GSH 24 h later, 100 and 200 microM increased gamma-GT activity 24 h later, but 800 microM decreased it. Restoration of intracellular GSH levels by addition of GSH to the culture medium completely prevented the increase in gamma-GT activity by BSO, while the addition of catalase or DMTU had no effect. We conclude that at least two effects are operating upon gamma-GT activity: GSH depletion seems to increase gamma-GT activity, while exposure to compounds generating oxidative stress correlates with a decrease in gamma-GT activity.
Animals↗
Effect of alveolar volume on the interpretation of single breath DLCO.
Single-breath carbon monoxide diffusing capacity in the whole lung (DLCO) and per unit alveolar volume (DLCO/VA), as expressed in percentage of normal values, gave discordant results when VA of the patients was abnormal. It was hypothesized that normal reference values were inappropriate to interpret data collected in such patients. To substantiate this hypothesis, DLCO and DLCO/VA were measured in four groups: (1) normal volunteers in whom both indices were measured at five different VA; (2) patients with high VA; (3) emphysematous patients; and (4) patients with diffuse interstitial lung diseases (DILD). In normal subjects, DLCO increased and DLCO/VA decreased with VA. In patients with overinflated lungs, the percentage of DLCO was more increased than DLCO/VA. In the emphysematous patients, both indices were equally decreased. In patients with DILD, DLCO was significantly more decreased than DLCO/VA in those suffering from a restrictive pattern. Theoretical values were re-calculated taking into account their true VA and using the relationships observed between DLCO, DLCO/VA and VA. The divergences between DLCO and DLCO/VA were strongly minimized. Therefore, the authors suggest the need to correct theoretical formulas in the presence of a restrictive pattern.
Adult↗
Putrescine uptake in rat type II pneumocytes correlates with gamma-glutamyltransferase activity.
gamma-Glutamyltransferase (gamma GT) is a key enzyme in glutathione metabolism and it is thought also to play a role in the uptake of polyamines such as putrescine. The aim of our study was to investigate if changes in gamma GT activity would alter total putrescine uptake [P(up)(tot)], as well as more specific uptake via the gamma GT pathway [P(up)(gamma GT)]. Forty-eight hours after their isolation, rat type II cells were exposed to 30, 60 or 125 microM L-buthionine-[SR]-sulfoximine (BSO) for 3 hr; 200 or 800 microM tertiary-butylhydroperoxide (t-BOOH) for 40 min; 10, 100 or 1000 microM paraquat (PQ) for 1 hr; and 60 or 85% O2 for 48 hr. The gamma GT activity, P(up)(tot) and P(up)(gamma GT) (assessed by inhibiting gamma GT) were measured immediately after the exposure to hyperoxia, or 24 hr after treatment with BSO, t-BOOH or PQ. From previous studies, it is known that these experimental conditions increased (BSO, 200 microM t-BOOH) or decreased (800 microM t-BOOH, PQ, hyperoxia) gamma GT activity. There was a strong correlation between the changes in gamma GT activity and the changes in P(up)(gamma GT) (r = 0.81, p < 0.001). These findings support the hypothesis that gamma GT partly regulates the uptake of putrescine, one of the polyamines required for cell growth and differentiation.
Animals↗
In vitro modulation of the P450 activities of hamster and human lung slices.
The respiratory tract is a portal of entry for many environmental chemicals. The respiratory tract plays an important role in the detoxification or metabolic activation of these chemicals, e.g., via cytochrome P450 enzymes. Alterations in the capabilities of these enzymes to metabolize inhaled compounds can, therefore, affect the toxicity of the chemicals. The pulmonary cytochrome P450 activity has been studied in many species, but relatively little is known about this activity in the human lung tissue. In this limited study, we have investigated the possibility of modulating in vitro the P450 activity in lung slices from hamsters and humans. The alkoxyresorufin-O-dealkylase activity was measured in the S9 fraction of lung slices incubated for 24 h with 10(6) mol/L 20-methylcholanthrene (3MC) or beta-naphthoflavone (beta N). The ethoxyresorufin-O-deethylase (EROD) activity was increased by 3MC and beta N in lung slices of both species. The benzyloxyresorufin-O-deethylase (BROD) activity was decreased after incubation with 3MC but increased with beta N. These data show that in vitro modulation in lung slices is feasible, although technical improvement is still needed, particularly in relation to the viability of the slices.
Animals↗
In vitro toxicity of cobalt and hard metal dust in rat and human type II pneumocytes.
It has been demonstrated that hard metal dust, which consists of a mixture of cobalt and tungsten carbide, is more toxic toward mouse peritoneal and rat alveolar macrophages than pure cobalt (Co) or tungsten carbide (WC). The aim of this study was to investigate the toxic effects of Co and hard metal dust on alveolar epithelial type II cells (AT-II), and to compare these with alveolar macrophages. Freshly isolated rat and human AT-II and rat alveolar macrophages were exposed for 18 hr to particles of Co, WC or Co/WC. As an index for cell toxicity, release of lactate dehydrogenase was measured. For rat AT-II, TD50 values per 10(5) cells were 672 micrograms (95% C.I. = 264-1706 micrograms) for pure Co and 101 micrograms (95% C.I. = 59-172 micrograms) for Co in Co/WC mixture. For rat alveolar macrophages, TD50 values per 10(5) cells were 18 micrograms (95% C.I. = 15-24 micrograms) for pure Co and 5 micrograms (95% C.I. = 5-6 micrograms) for Co in Co/WC mixture. WC only caused an increase in lactate dehydrogenase at high concentrations. No toxicity was found in human AT-II for either Co, WC or Co/WC. These results indicate that 1) rat AT-II are less sensitive to Co than rat alveolar macrophages, 2) human AT are less sensitive to Co than rat AT-II, 3) the toxicity of Co is increased by the presence of WC.
Animals↗
Pulmonary toxicity of components of textile paint linked to the Ardystil syndrome: intratracheal administration in hamsters.
OBJECTIVES: It was hypothesised from an epidemiological investigation that a formula change from Acramin FWR (a polyurea) to Acramin FWN (a polyamide-amine) had led to severe pulmonary disease in textile printing sprayers in SPAIN AND ALGERIA. To verify this, the pulmonary toxicity of the components of the paint systems involved was assessed in experimental animals. METHODS: Individual components and relevant mixtures, diluted in phosphate buttered saline, were given by intratracheal instillation of 2 ml/kg to hamsters. Pulmonary toxicity was assessed on days 3, 7, 14, 28, and 92 after a single intratracheal instillation, by histology and by measuring wet and dry lung weight, protein concentration, the activities of lactate dehydrogenase, alkaline phosphatase, beta-N-acetyl-glucosaminidase, and gamma-glutamyltransferase, inflammatory cell number and distribution in bronchoalveolar lavage fluid (BALF), and hydroxyproline content in dried lung tissue. RESULTS: Based on the doses that killed 50% of the animals (LD50s), the various components were found to be 10 to 1250 times more toxic when given intratracheally than when given orally (according to reported oral LD50s in rats). Acramin FWN, Acramin FWR, Acrafix FHN, or their mixtures caused lung damage. Protein concentration, enzyme activities, total cell number, and percentage of polymorphonuclear neutrophils were increased in BALF during the first week after intratracheal instillation. Lung weights remained high for at least a month. Histology showed inflammatory cell infiltration and subsequent fibrosis with collagen deposition. This finding was confirmed by an increased hydroxyproline content in dried lung tissue. Acramoll W did not show toxic effects. CONCLUSIONS: The study suggests that there is no major difference, in hamsters, between the acute intratracheal toxicity of Acramin FWR and that of Acramin FWN. Consequently, there is no simple toxicological explanation for the epidemiological hypothesis. However, the pulmonary toxicity of these non-irritant polymeric compounds is surprisingly high. The Ardystil disaster and these results should serve as a strong warning that conventional toxicity testing of chemicals does not necessarily protect workers against respiratory toxicity.
Acetylglucosaminidase↗
Involvement of an NAD(P)H oxidase-like enzyme in superoxide anion and hydrogen peroxide generation by rat type II cells.
BACKGROUND: Although alveolar macrophages are considered to be the primary cellular mediators of host defence in the lung, there is increasing evidence that type II cells may also play an active role in host defence. A study was undertaken to investigate whether type II cells generate O2-. and H2O2 via an NADPH oxidase-like system and whether exposure of the type II cells to soluble or particulate stimuli known to activate NADPH oxidase in macrophages also leads to increased production of H2O2. METHODS: Rat type II cells and alveolar macrophages were exposed to 10, 100, or 1000 nM phorbol-12-myristate-13-acetate (PMA) and the production of O2-. and H2O2 was determined by chemiluminescence. Thirty minutes before stimulation with 1 microM PMA type II cells were also exposed to the same concentrations of a protein kinase C (PKC) antagonist GF109203x, the non-selective protein kinase inhibitor staurosporine (1, 10, or 100 nM), or the NADPH oxidase inhibitor diphenyliodonium chloride (DPI) (1, 10, 100, or 1000 microM). The effects of arachidonic acid, zymosan and Staphylococcus aureus on H2O2 production were determined. Cell membrane fractions from type II cells and macrophages were assayed for NADPH oxidase activity. RESULTS: After exposure to 1 microM PMA, O2-. and H2O2 generation increased 6.3-fold and 9.0-fold, respectively, in type II cells and 2.4-fold and 5.2-fold, respectively, in macrophages. In contrast to the macrophages, the increase in O2-. and H2O2 generation by type II cells was completely prevented by 1 mM KCN. Preexposure to GF109203x, staurosporine, or DPI completely prevented the rise in O2-. and H2O2 generation. Mean (SD) NADPH oxidase activity of 138 (38) nmol O2-./min/mg protein was found in membrane fraction I of the type II cells, and 102 (31) nmol O2-./min/mg protein in fraction II. Macrophages showed higher NADPH oxidase activity in membrane fraction II. In type II cells exposure to arachidonic acid led to a significant 5.3-fold increase in H2O2 generation, exposure to zymosan increased H2O2 generation 46-fold, and exposure to S aureus 25-fold with a maximum 30-50 minutes after addition of the bacteria. CONCLUSIONS: Type II cells generate O2-. and H2O2 via a PKC-mediated activation of an NAD(P)H oxidase-like membrane bound enzyme. Arachidonic acid, zymosan, and bacteria also give rise to increased H2O2 production. Type II cells might thus play an active role in host defence.
Animals↗
Changes in gamma-glutamyltransferase activity in rat lung tissue, BAL, and type II cells after hyperoxia.
The effect of hyperoxia on gamma-glutamyltransferase (gamma-GT), an important enzyme for the uptake of precursor molecules for intracellular synthesis of glutathione (GSH), has not been established. Our aim was to investigate the effects of prolonged subtoxic levels of hyperoxia on gamma-GT activity and GSH levels in lung tissue, epithelial lining fluid (ELF), and isolated rat type II cells immediately after their isolation and 48 h later when kept in culture in normoxia. Seventeen male Wistar rats were divided in three groups (n = 5-7) and were exposed to air or to 60 or 85% O2 for 7 days. Pulmonary gamma-GT activity increased in the 60 and 85% O2-exposed animals (1.6- and 3.2-fold, respectively), and tissue GSH levels increased only in the 60% O2 group (1.3-fold). In isolated type II cells from 60 and 85% O2-exposed animals, gamma-GT activity decreased by -70 and -88%, respectively, which was supported by cytochemical staining. Type II cell gamma-GT mRNA expression tended only to decrease after 85% O2. Type II cell gamma-GT activity strongly correlated with ELF gamma-GT (r = 0.60, P < 0.001), and ELF gamma-GT strongly correlated with ELF GSH (r = 0.75, P < 0.0001). When in culture, type II cell gamma-GT activity and GSH levels remained, respectively, 2.5- and 1.9-fold lower in the 60% O2-exposed group, but, in the 85% O2-exposed group, gamma-GT activity increased 2.1-fold, and GSH levels dropped to the levels of the control cells. Hyperoxia led to a concentration-dependent decrease in gamma-GT activity in rat type II cells, possibly by direct inactivation, but led to an increase in whole lung tissue gamma-GT. There seemed to be a negative feedback between intracellular GSH levels and type II cell gamma-GT activity. gamma-GT levels in the ELF were correlated with type II cell gamma-GT activity, but ELF gamma-GT did not seem to play an active role in the regulation of the ELF GSH pool. Hyperoxia decreased ELF GSH levels, possibly by increased degradation of GSH in the parenchymal lung tissue as a result of the increased gamma-GT activity.
Alkaline Phosphatase↗
N-acetylcysteine does not protect against type II cell injury after prolonged exposure to hyperoxia in rats.
Although the antioxidant properties of N-acetylcysteine (NAC) in vitro are widely accepted, the efficacy of NAC in the prevention of O2 toxicity in vivo is poorly documented. The aim of our study was to investigate the presumed protective effect of NAC on hyperoxic lung injury, focusing on gamma-glutamyltransferase (gamma-GT) activity and glutathione (GSH) levels in lung tissue, epithelial lining fluid (ELF), and isolated rat type II cells immediately after their isolation and 48 h later when kept in culture in normoxia. Thirty-four male Wistar rats were divided in three groups (n = 10-14) and were exposed to air or to 60 or 85% O2 for 7 days. One-half of the rats in each group received 200 mg/kg NAC intraperitoneally one time per day from 3 days before exposure until the end of the experiment, and the other one-half received the vehicle. In the 85% O2-exposed animals, NAC led to more respiratory distress and weight loss. NAC did not prevent the rise in bronchoalveolar lavage lactate dehydrogenase and alkaline phosphatase, but it did prevent the rise in calculated ELF volume. NAC decreased GSH levels (1.4-fold) and gamma-GT activity (1.8-fold) in the air-exposed type II cells. In the 60% O2-exposed group, no effects of NAC were seen (except for a decrease in gamma-GT mRNA expression), but, in the 85% O2-exposed group, NAC gave rise to higher GSH (2.6-fold) and higher gamma-GT activity (2.9-fold) in the ELF and lower GSH (6.9-fold) and higher gamma-GT activity (3.6-fold) in the type II cells. Even in culture, GSH levels remained 1.5-fold lower than in the cells from the air-exposed animals and 2-fold lower than in the cells from the 85% O2-exposed animals. There was increased DNA damage (as assessed by thymidine incorporation) and apoptosis after hyperoxia, especially after 60% O2, and this effect was amplified after NAC treatment. Although protective at the endothelial side, NAC treatment led to adverse effects at the epithelial side, despite, or probably because of, restoration of the ELF GSH levels in the presence of high O2 levels. Because NAC is rapidly metabolized to cysteine, it is plausible that the effects of NAC are manifested through the toxic effects of cysteine.
Acetylcysteine↗
Effects of oxygen pressure and medium volume on the toxicity of paraquat in rat and human type II pneumocytes.
The herbicide, paraquat is highly toxic for mammals, with the lungs being the main target organ, because of the active accumulation of the compound in this organ. The cellular toxicity of paraquat has been shown to be an O2-driven process and hyperoxia is known to increase the lethality of paraquat. In this study we have examined the effect of various O2 concentrations on the toxicity of paraquat in rat and human type II pneumocytes in culture, and we have tested whether the thickness of the liquid layer above the cells would influence the toxicity of paraquat. Type II pneumocytes were isolated from rat or human lung tissue using trypsin digestion, percoll density gradient centrifugation and differential attachment. Adherent cells (day 2) were incubated for 20 h in different volumes of culture medium (thickness of liquid layer), whether or not in the presence of paraquat, in the presence of different O2 tensions. The viability of the cells was assessed by the release of LDH in the culture medium. In both rat and human type II pneumocytes the toxicity of paraquat was independent of the thickness of the liquid layer (2.5 to 10 mm height). The toxicity of paraquat in rat type II pneumocytes decreased from a TC50 value of 28 microM paraquat at 21% O2 to 107 microM at 10% O2 and increased to 12 microM and 8 microM at 60% and 85% O2, respectively. For human type II pneumocytes the TC50 values were 7 microM; 25 microM and > 1000 microM paraquat at 60%, 21% and 10% O2, respectively. In this study we have shown that the diffusion of O2 through a liquid layer does not limit the toxicity of paraquat and that, as in vivo, increasing O2 partial pressure enhances the toxicity of paraquat.
Animals↗