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M Emura

Publications and source records attributed to M Emura.

At least 19 recordsLinked to original sources
PubMed2003

Inhalation toxicity of propineb. Part II: Results of mechanistic studies in rats.

Previous repeated inhalation exposure studies revealed two independent organotropic effects of inhaled propineb dust: One was restricted to the lung, the other to muscle weakness of hindlimbs. These effects were believed to be causally related to the principle decomposition products of this type of dithiocarbamate in the biological milieu and related to zinc and carbon disulfide. Two mechanistic 1-wk inhalation studies were performed, each focusing on one of these findings. The 7 x 6-h/day repeated-exposure inhalation study analyzed whether the nature of the response occurring at the alveolar level is "adaptive" or "early adverse" and whether soluble zinc is the causative agent. Groups of 18 female rats were exposed nose-only to mean concentrations of 0, 1.1, 5.5, and 25.8 mg propineb/m(3) and 6.9 mg ZnO/m(3). On postexposure days 1, 3, and 15 the time course of responses was analyzed by bronchoalveolar lavage (BAL), including quantification of Zn and metallothionein (MT) in BAL cells. Clinical evidence of muscular weakness was investigated separately in 20 female Wistar rats exposed to 70 mg propineb/m(3) on 5 consecutive days (6 h/day), followed by a 2-wk postexposure period. Clinical signs, body weights, and feed and water consumption were recorded as frequently as technically feasible. Fifty percent of rats received an oral cysteine supplementation to verify/refute the hypothesis that the incapacitation observed in previous studies is the cause of emaciation and associated impairment of CS(2) detoxification. The findings of the first study are consistent with this hypothesis, namely, that soluble Zn triggers a series of pulmonary events that is consistent with the homeostasis of this essential metal. It is concluded, accordingly, that the adjusted maximal workplace level for ZnO is also valid for propineb to preclude Zn-mediated responses to occur in the lung. With respect to muscular effects, this mechanistic study demonstrates further that the increased detoxification capacity afforded by oral supplementation of cysteine mitigates markedly the toxic potency of propineb. Procedural variables specific to the inhalation bioassay appear to be decisive for the elicitation of muscular effects. The major variable is considered to be the large drop in body weights associated with each exposure session and the concomitantly decreased uptake of essential nutritional factors (e.g., cysteine) involved in the detoxification of this compound. Accordingly, the muscular deficits elicited by high concentrations of propineb are viewed to be secondary effects in an animal species likely to be more susceptible to this type of change than humans (Pauluhn & Rosenbruch, 2003).

Administration, Inhalation↗
PubMed2000

Respiratory sensitization to diphenyl-methane-4,4'-diisocyanate (MDI) in guinea pigs: impact of particle size on induction and elicitation of response.

The impact of particle size of aerosolized polymeric diphenylmethane-4,4'-diisocyanate (MDI) for the induction and elicitation of respiratory sensitization was evaluated. Four groups of 16 female guinea pigs each received either the vehicle, repeated intradermal (id) injections (3 x 0.3% MDI), one high-level inhalation exposure of 15 min to 135 mg MDI/m(3) air using a small aerosol (MMAD approximately 1.7 microm) or large aerosol (MMAD approximately 3.8 microm). Three weeks later, animals were challenged subsequently with two ramped concentrations of MDI aerosol (average concentrations 16 and 49 mg/m(3) air, each for 15 min) and two different particle sizes, i.e., the MMAD was either approximately 1.6 microm or approximately 5.1 microm for the small- and large-size aerosol, respectively. Respiratory sensitization was assessed by two endpoints: the measurement of respiratory rate, and examination of influx of eosinophilic granulocytes into the mucosa and submucosa of the trachea, bronchi, and lung-associated lymph nodes (LALN). The recruitment of eosinophilic granulocytes into bronchial tissues was subdivided as follows: muscularis mucosae, submucosa, and perivascular. From measurements of respiratory rate, it would appear that guinea pigs sensitized by id injections or by inhalation exposure with the large aerosol tended to display a higher responsiveness than naive controls when challenged with the small aerosol. The recruitment of eosinophilic granulocytes in the bronchial tissue was greater in both inhalation induction groups as compared to the vehicle control. It appears that there was a somewhat greater response in animals sensitized by id injections or by inhalation exposure with the large aerosol and challenged with the small aerosol. Topographically, this difference was apparent only at the bronchial perivascular level and lung-associated lymph nodes (LALN), whereas at the submucosal and muscularis mucosae level the impact on particle size tended to be less pronounced. In summary, this study suggests that a brief, high-level inhalation exposure of MDI aerosol caused a sensitization of bronchial tissues in guinea pigs. The higher sensitization potency of the large aerosol may possibly be related to a dosimetric phenomenon because of the greater fraction of deposition of large particles within the upper respiratory tract. Overall, challenge exposures with this type of irritant aerosol appear to evoke more consistent effects when the MMAD is in the range of approximately 2 rather than approximately 5 microm.

Administration, Inhalation↗
PubMed1999

Two-week inhalation toxicity of polymeric diphenylmethane-4, 4'-diisocyanate (PMDI) in rats: analysis of biochemical and morphological markers of early pulmonary response.

The pulmonary response of Wistar rats to respirable polymeric diphenylmethane-4,4'-diisocyanate (PMDI) aerosol was examined in a 2-wk repeated nose-only inhalation exposure study. Exposure concentrations were 1.1, 3.3, and 13.7 mg PMDI/m(3) (6 h/day, 15 exposures). The level of 13.7 mg/m(3) was actually a combination of an initial target concentration of 10 mg/m(3) in wk 1, which was raised to 16 mg/m(3) in wk 2, due to a lack of signs suggestive of pulmonary irritation. An acute sensory irritation study on rats served as basis for selection of these concentrations. Shortly after the 2-wk exposure period, rats were subjected to pulmonary function and arterial blood gas measurements. Lungs were examined by light and transmission electron microscopy, and labeling indices in terminal bronchioles were measured. Bronchoalveolar lavage (BAL) was performed to assess various indicators of pulmonary inflammation, including neutrophil and macrophage numbers, protein, lactate dehydrogenase (LDH), gamma-glutamyltranspeptidase (gamma-GT), alkaline phosphatase (APh), acid phosphatase (ACPh), and beta-N-acetylglucosaminidase (beta-NAG). Phosphatidylcholine in BAL fluid and BAL cells was determined as aggregated endpoint suggestive of changes in pulmonary surfactant. Rats exposed to 3.3 and 13.7 mg/m(3) experienced concentration-dependent signs of respiratory tract irritation. Determination of arterial blood gases, lung mechanics, and carbon monoxide diffusing capacity did not demonstrate specific effects. Analysis of BAL fluid and BAL cells revealed changes indicative of marked inflammatory response and/or cytotoxicity in rats exposed to 13.7 mg/m(3), and the changes were characterized by statistically significantly increased activities of LDH, beta-NAG, and protein. Phospholipid concentrations were increased in rats exposed to 1.1 mg/m(3) and above (elevated levels of lipid material in alveolar macrophages demonstrated by polychrome stain) and 3.3 mg/m(3) and above (increased intracellular ACPh activity and intracellular phospholipids). In these groups, gamma-GT was statistically significantly increased. These findings suggest that changes in phospholipid homeostasis appear to occur at lower levels than those eliciting inflammation and cytotoxicity. Light and transmission electron microscopy suggest that exposure to 3.3 and 13. 7 mg/m(3) resulted in focal inflammatory lesions and an accumulation of refractile, yellowish-brownish material in alveolar macrophages with concomitant activation of type II pneumocytes. In the terminal bronchioles a concentration-dependent increase of bromodeoxyuridine (BrdU)-labeled epithelial cells was observed in all PMDI exposure groups. In summary, it appears that respirable PMDI aerosol interacts with pulmonary surfactant, which, in turn, may stimulate type II pneumocytes to increase their production of surfactant and to proliferate.

Allergens↗
PubMed1997

Stem cells of the respiratory epithelium and their in vitro cultivation.

Parenchymal (epithelial or mesenchyma) stem cells are rapidly drawing both scientific and clinical attention in solid organs like the liver, skin, intestine and abdominal mesothelium, just as has been the case in the hematopoietic system. For the stem cells of these organs various definitions, markers for identification, methods of isolation and in vitro cultivation, and lineage mechanisms have been proposed and some of them are now proven to be valid and useful. In this article attempts will be made to explore whether there are stem cells in the lower respiratory system (from the trachea to the lung periphery) and what they look like. Because of its anatomical and functional complexity the stem cell concept for the respiratory system has been developing rather slowly. Nevertheless, the data available seem to indicate that in analogy to the above mentioned organs there is only one type of epithelial stem cells throughout all sections of the lower respiratory system during fetal through adult stages. They are multipotent for cell differentiation and able to yield lineage progenitors for ciliated, goblet, basal. Clara neuroendocrine, alveolar type 1 and alveolar type 2 cells.

Animals↗
PubMed1997

Formation and persistence of the miscoding DNA alkylation product O6-ethylguanine in male germ cells of the hamster.

The cellular parameters which modulate trans germ-line carcinogenesis by DNA-reactive agents have not yet been studied in detail. Therefore, we have measured in this study the formation and repair kinetics of the miscoding alkylation product O6-ethylguanine (O6-EtGua) in nuclear DNA of spermatogonial cells of the Syrian golden hamster (SGH) after exposure to either of two potent N-nitroso carcinogens, ethylnitrosourea (ENU) or diethylnitrosamine (DEN). Both compounds, the spontaneously decomposing ENU, and DEN, which has to be converted by cellular enzymes to the reactive ethyl diazonium ion, induce the same pattern of alkylation products in nuclear DNA. Adduct analyses were performed at the single-cell level by using a quantitative immunocytological assay and anti-(O6-EtGua) monoclonal antibodies. 1.5 h after intraperitoneal application of ENU (100 microg/g body weight) O6-EtGua levels in the nuclear DNA of spermatogonia were similar to those in other cell types of the same hamster. About 30% of the initially formed DNA adducts were still persistent in spermatogonial cells even 4 days after ENU exposure. The presence of O6-EtGua in DNA after exposure to DEN (100 microg/g body weight) implies the capability of hamster spermatogonial cells to convert nitrosamines into DNA-alkylating metabolites. This capability of male germ cells in combination with their limited repair capacity for a critical DNA adduct and their high rate of proliferation may be considered as a major risk factor for genetic effects including carcinogenesis in subsequent generation(s).

Animals↗
PubMed1996

In vitro reconstituted tissue as an alternative to human respiratory tract.

The data obtained from in vitro systems utilizing human cells and tissues should form a basic part of the information necessary for risk assessment. The most important thing for such systems is, therefore, to simulate the structures and functions of cells and tissues in the native organ as closely as possible. In designing in vitro systems, there may be two approaches-one aiming at the growth of cells in a primarily two-dimensional fashion, the other allowing cells to form in vivo-mimicking three-dimensional architectures. In cultures in which the airway epithelial cells are growing in a two-dimensional fashion, some functional and structural characteristics can be developed to a considerable extent. However, there are some that cannot be developed or expressed under that condition but require a three-dimensional growth pattern. In this paper we explore the capacity of early to long-term passage airway epithelial cells (human and hamster) to resume architectures and functions existing in the native tissue in the specific environments given in vitro.

Animals↗
PubMed1996

Sensitivity of a hamster lung cell line to direct and indirect acting carcinogens.

Cytotoxicity of benzo(a)pyrene (B(a)P), 7,12-dimethylbenz(a)anthracene (DMBA), aflatoxin B1 (AB1), and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was estimated in vitro by using a hamster lung cell line. The studies were conducted to assess the usefulness of an organ-specific cell culture system for demonstrating differences in the cytotoxic potency of diverse chemical carcinogens. Cytotoxicity was determined by using the succinate dehydrogenase assay (MTT assay) after different incubation times and concentrations with the corresponding carcinogens. The effective concentration EC50 as well as the slope of the regression line were used as parameters for the biological effects. The results from these studies indicate a clear dose-dependent reaction after incubation of the cells with aflatoxin B1 (EC50: 2.3 microM) and MNNG (EC50: 4.0 microM). For the polycyclic hydrocarbons benzo(a)pyrene and DMBA, a dose-independent reaction was found. These results indicate that consideration of the EC50 values only might not be sufficient to characterize differences in the cytotoxic activity of different substances. Chemicals can lead to equal values in the EC50, but cells can differ significantly in their biological sensitivity, meaning that the extent of reduction in cell proliferation depends on the chemical used. By considering the two above-mentioned parameters, a ranking for the analyzed substances will be possible in the following way: AB1, MNNG, DMBA and B(a)P. Taken together, our experiments show that it is possible to reveal differences in the cytotoxic potency of chemicals by using in vitro methods.

Animals↗
PubMed1996

[Two cases of recurrent, massive hemoptysis with contralateral, concurrent hemoptysis].

Bilateral, concurrent massive hemoptysis with respiratory failure is rare and difficult to manage. We encountered two patients with this condition. One was a 51-year-old woman and one was a 63-year-old woman. Both had inactive pulmonary tuberculosis and episodes of hemoptysis. Home oxygen therapy was prescribed to the former patient and bronchial artery embolization was done in the latter. The sites of initial bleeding were in the left basal segment and in the lingular segment. Bleeding was well controlled by endobronchial tamponade with a Fogarty balloon catheter in the left main bronchus, contralateral intubation, and systemic artery embolization. Use of water instead of air in the balloon was more effective in over the long term. Concurrent bleeding from the contralateral upper lobe bronchus was controlled by compression with a tracheal tube cuff at the bronchial orifice. Afterward, an infiltrative shadow was seen on the chest X-ray film and hemoptysis occurred in case 2 occurred in case 2. Treatment with erythromycin and antituberculosis drugs brought about improvement of chest X-ray findings and disappearance of the hemoptysis.

Antitubercular Agents↗
PubMed1995

Increased risk of cancer in the descendants of Syrian hamsters exposed prenatally to diethylnitrosamine (DEN).

Transmission of site-specific tumorigenicity (papillomas in larynx and trachea) of diethylnitrosamine (DEN) to the 2 subsequent generations (F1 and F2) was studied using an outbred strain (Han:AURA) of pregnant Syrian golden hamsters (P generation), which were treated i.p. with 10 mg/kg b.w. of DEN on day 12, 13 or 14 of gestation. Laryngotracheal papillomas were induced by DEN in the P and F1 generations only, while these tumours did not occur in the F2 generation. Spontaneously occurring tumours, including uterine adenocarcinomas, lymphomas, and laryngotracheal neuro-endocrine cell tumours, were observed at higher incidences among the F2 animals derived from the P generation hamsters treated with DEN only on day 13 or 14 of gestation. In the same animals, the ratio of malignant to benign tumours was considerably higher than in controls. In addition, the F2 hamsters derived from the DEN-treated P generation showed more frequent multiple organ involvement in tumorigenesis than the F2 controls. Several uncommon malignant tumours were detected in the F2 offspring, possibly the result of damage caused to germ cells by the prenatal exposure of F1 Syrian hamsters to DEN.

Animals↗
PubMed1995

Formation of O6-ethylguanine in spermatogonial DNA of adult Syrian golden hamster by intraperitoneal injection of diethylnitrosamine.

17-Week-old Syrian golden hamsters received a single intraperitoneal injection of diethylnitrosamine (DEN) at a dose of 100 mg/kg body weight. The DNA alkylation product O6-ethylguanine was formed in the spermatogonia. The data demonstrate that DEN can pass the blood-testis barrier and be metabolized in the spermatogonia to yield an alkylating derivative or that externally activated metabolites themselves can pass the barrier.

Animals↗
PubMed1994

Neuroendocrine phenotype differentiation in a hamster lung epithelial cell line under low oxygen pressure or after transformation by diethylnitrosamine.

Oxygen pressure as low as 5% in the gas phase or 87 mmHg in the liquid phase induced various neuroendocrine cell (NEC) phenotypes in more than 80% of cells of a cloned fetal Syrian hamster lung epithelial cell line (M3E3/C3). Further, cells from a number of colonies transformed in an anchorage-independent manner by diethylnitrosamine (DEN) demonstrated a NEC phenotype. Since the cell line used is of a pluripotent stem cell type, both hypoxia and DEN appear to possess a potency for NEC phenotype induction.

Animals↗
PubMed1994

Comparison of biological effects of different polycyclic aromatic hydrocarbons in lung cells of hamster and rat in vitro.

The cytotoxicity and frequencies of transformation induced by 5 environmental polycyclic aromatic hydrocarbons (PAH) in hamster (M3E3/C3) and rat (WRB K3) lung cells were compared. Both cell strains investigated here retain major metabolic characteristics of the target cells in vivo and are thus able to effectively metabolize, i.e. activate, PAH. Cytotoxic effects of the carcinogen were determined in colony-forming assays and the PAH tested induced dose-dependent cytotoxic responses in the M3E3/C3 and WRB cells. They could then be classified into strong and weak cytotoxicity. Compared to the hamster cell system, the WRB cells were generally shown to be more sensitive. The transforming capacity of the compounds was determined by a soft agar colony formation assay detecting cells with anchorage independency (AI). All PAH investigated induced transformation to AI growth in both cell systems. The transforming activity of the PAH, relative to benzo[a]pyrene (B[a]P) as a reference substance, was determined to facilitate their ranking. This order of transforming potency appears to be similar to that observed in animal studies.

Animals↗