RESUMO
Toluene diisocyanate (TDI), a highly reactive industrial chemical is one of the leading causes of occupation-related asthma in industrialized countries. The pathophysiology of TDI-induced asthma, however, remains poorly understood, in part due to a lack of appropriate animal models. In this study, four models of TDI-sensitised mice were investigated. In model number 1, the mice were sensitised for 4 h/day on four consecutive days to 3 ppm inhaled TDI and challenged twice for 4 h each time with 0.3 ppm inhaled TDI. In model number 2, the sensitising condition was similar to that of model 1, but the challenge conditions involved an initial inhalation of 2 ppmTDI for 4h and then tracheal instillation with 50 microg/mouse albumin-TDI. In model number 3, the mice were sensitised first to 25% TDI (sc) and then three times for 4 h each time to 1 ppm inhaled TDI and challenged twice for 4h each time with 0.1 ppm inhalated TDI. In model number 4, the mice were first sensitised to 1% TDI by skin application and then with 0.2% TDI by tracheal instillation and challenged tree times by tracheal instillation of 0.1% TDI. In model number 4, skin application followed by tracheal instillations of TDI led to local and systemic Th2-dominated immune responses that were characterized: (1) in the lung-associated lymph nodes by a decrease in Th1 cytokine (IFN-gamma) production associated with an increase in Th2 cytokine (IL-4, IL-5, IL-3) production; (2) in the lungs by an allergic inflammation throughout the conducting airways: goblet cell proliferation and eosinophil influx and; (3) in the serums by increased total and specific IgE levels, 17.5- and 3.5-fold higher than that of the controls, respectively. The conditions used for sensitisation in the other models, i.e. inhalation or subcutaneous administration plus inhalation, failed to induce a strong Th2 response like that observed in model number 4. The findings indicate that TDI can induce a Th2-dominated response in mice when administered by topical application plus tracheal instillation for sensitisation and by intra-tracheal instillation for challenge (model number 4). This mouse Th2 model of TDI-induced airway allergy can, in several aspects, mimic occupational TDI asthma in humans and may prove to be useful in determining the mechanistic basis behind this disease.
Assuntos
Modelos Animais de Doenças , Hipersensibilidade Respiratória/induzido quimicamente , Células Th2/imunologia , Tolueno 2,4-Di-Isocianato/toxicidade , Administração Tópica , Animais , Brônquios/efeitos dos fármacos , Brônquios/imunologia , Brônquios/patologia , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/imunologia , Eosinófilos/citologia , Feminino , Imunoglobulina E/sangue , Exposição por Inalação , Injeções Subcutâneas , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologiaRESUMO
Occupational allergy and asthma is a challenging issue in the developing countries. Chemicals inhaled in the workplaces may act not only as allergens but also as immune response modifiers, contributing to asthma exacerbation. In this study, we tested the adjuvant effect of 20 ppm chloroform, 10 ppm 1,1-dichloroethylene, and 100 ppm styrene in mice. Female BALB/c mice were sensitised to ovalbumin (OVA) without using alum. During the OVA-sensitisation period, these mice were exposed by inhalation to the chemicals studied for 6h/day for four consecutive days. After two OVA-intratracheal challenges, a mild Th2 immune response was observed in the OVA-exposed groups. This response was characterised by a mild increase in serum specific IgE level, in local Th2 cytokine production, and in lung inflammatory reaction. Exposure to styrene or chloroform alone slightly increased Th2 cytokine production by lung-draining lymph node cells cultured with concanavaline A, except for the IL-4 level in the chloroform exposure group, which decreased. On the other hand, exposure to 1,1-dichloroethylene alone markedly increased the Th2 cytokine levels compared to those observed in the groups exposed to OVA alone. In the combined OVA+chemical-treated groups, styrene potentiated IL-4, -5 and -13 production efficiently (approximately two, four and three times higher, respectively), resulting in an increase in the total IgE levels and inflammatory reaction. On the other hand, the enhanced IgE levels and the exacerbation of the inflammatory response by 1,1-dichloroethylene or chloroform were associated with only minor changes in local cytokine levels. These findings suggest that exposure to chemicals through inhalation may aggravate the allergic lung inflammation. And this, depending on the chemical exposure conditions, may result from the synergistic effect of chemicals and allergen on local Th2 cytokine production.
Assuntos
Inflamação/patologia , Exposição por Inalação/efeitos adversos , Ovalbumina/imunologia , Hipersensibilidade Respiratória/patologia , Compostos de Alúmen/toxicidade , Animais , Asma/patologia , Clorofórmio/administração & dosagem , Clorofórmio/toxicidade , Citocinas/metabolismo , Dicloroetilenos/administração & dosagem , Dicloroetilenos/toxicidade , Ensaio de Imunoadsorção Enzimática , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Imunoglobulina E/metabolismo , Interleucinas/metabolismo , Pulmão/patologia , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Solventes/administração & dosagem , Solventes/toxicidade , Estireno/administração & dosagem , Estireno/toxicidade , Células Th2/efeitos dos fármacos , Células Th2/imunologiaRESUMO
Road paving workers are exposed to bitumen fumes (CAS No. 8052-42-4), a complex mixture of volatile compounds and particles containing carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons. However, epidemiological and experimental animal studies failed to draw unambiguous conclusions concerning their toxicity. In order to gain better insights on their genotoxic potential, we used an experimental design able to generate bitumen fumes at road paving temperature (temperature: 170 degrees C, total particulate matter: 100mg/m3) and perform a nose-only exposure of Big Blue transgenic rodents 6h/day for five consecutive days. The mutagenic properties of bitumen fumes were determined by analyzing the mutation frequency and spectrum of the neutral reporter gene cII inserted into the rodent genome. We previously observed in mouse lung, that bitumen fumes did not induce an increase of cII mutants, a modification of the mutation spectrum, nor the formation of DNA adducts. Since DNA adducts were found in the lungs of rats exposed to asphalt fumes in similar conditions, we decided to carry out an analogous experiment with Big Blue rats. A DNA adduct was detected 3 and 30 days after the end of treatment suggesting that these genetic alterations were quite steady. Thirty days after exposure, the cII mutant frequency was similar in control and exposed rats. In addition, a slight but not significant modification of the mutation spectrum associated with an increase of G:C to T:A and A:T to C:G transversions was noticeable in the treated animals. Then, these data failed to demonstrate a pulmonary mutagenic potential for bitumen fumes generated at road paving temperature in our experimental conditions despite the presence of a DNA adduct. These results may provide information concerning the pulmonary mechanism of action of this aerosol and may contribute to the occupational health hazard assessment.
Assuntos
Hidrocarbonetos/toxicidade , Exposição por Inalação , Pulmão/patologia , Mutagênicos/toxicidade , Animais , Animais Geneticamente Modificados , Pareamento de Bases , DNA/efeitos dos fármacos , DNA/genética , DNA/isolamento & purificação , Pulmão/efeitos dos fármacos , Mutação , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Deleção de Sequência , VenezuelaRESUMO
Both noise and styrene can injure the cochlea, resulting in a reduction of incoming inputs from the cochlea to the central nervous system. In addition, styrene is known to have neurotoxic properties at high doses. The loss of inputs caused by noise has been shown to be compensated by a new equilibrium between excitatory and inhibitory influences within the inferior colliculus (IC). The main goal of this study was to determine whether styrene-induced hearing loss could also be counterbalanced by a GABAergic adjustment in the IC. For this purpose, rats were exposed to noise (97 dB SPL octave band noise centered at 8 kHz), or to a non-neurotoxic dose of styrene for 4 weeks (700 ppm, 6 h/day, 5 days/week). Auditory sensitivity was tested by evoked potentials, and cochlear damage was assessed by hair cell counts. Glutamate decarboxylase (GAD) was dosed in the IC by indirect competitive enzyme-linked immunosorbent assay. Both noise and styrene caused PTSs that reached 27.0 and 14.6 dB respectively. Outer hair cell (OHC) loss caused by noise did not exceed 9% in the first row, on the other hand OHC loss induced by styrene reached 63% in the third row. Only the noise caused a decrease of GAD of 37% compared to that measured in the controls. No significant modification of GAD concentration has been shown after styrene exposure. Thus, central compensation for cochlear damage may depend on the nature of the ototoxic agent. Unless styrene directly affects IC function, it is reasonable to assume that noise causes a modification of inhibitory neurotransmission within the structure because of impairment of afferent supply to the auditory brainstem. The present findings suggest that central compensation for cochlear damage can preferably occur when afferent fibers are altered.
Assuntos
Cóclea/efeitos dos fármacos , Cóclea/lesões , Glutamato Descarboxilase/metabolismo , Perda Auditiva/induzido quimicamente , Colículos Inferiores/enzimologia , Isoenzimas/metabolismo , Ruído , Estireno/farmacologia , Ferimentos e Lesões/enzimologia , Animais , Audiometria , Limiar Auditivo , Cóclea/patologia , Ensaio de Imunoadsorção Enzimática , Potenciais Evocados Auditivos , Células Ciliadas Auditivas/patologia , Perda Auditiva/diagnóstico , Perda Auditiva/enzimologia , Perda Auditiva/patologia , Perda Auditiva Provocada por Ruído/diagnóstico , Perda Auditiva Provocada por Ruído/fisiopatologia , Testes Auditivos , Masculino , Ratos , Ratos Long-Evans , Ferimentos e Lesões/patologiaRESUMO
There is clear evidence that aromatic solvents can disrupt the auditory system in humans and animals. As far as animal models are concerned, solvent-induced hearing loss seems to be species-dependent. Indeed, most published data have been obtained with the rat, which shows mid-frequency cochlear deficits, whereas the guinea pig does not show any permanent hearing loss after solvent exposure. In the current investigation, the effects of two solvents, toluene (600 ppm) and styrene (1000 ppm), were studied in both Long-Evans rats and pigmented guinea pigs exposed 6 h/day for 5 consecutive days. Cochlear function was tested by using distortion product otoacoustic emissions (DPOAE) measured prior to the solvent exposure, 20 min after the end of the exposure and successively at 2 and 4 weeks post-exposure. In addition to cochlear testing, solvent concentrations in blood and urinary metabolites were measured. A cochlear histological analysis was performed at the end of the experiment. No decrease in DPOAE amplitude was observed in the guinea pig, even immediately following the end of exposure. The rat model showed severe disruption of auditory function and cochlear pathology, whereas the guinea pig had no disruption of DPOAE or cochlear pathological alterations. Therefore, the vulnerability of the cochlear function was strictly dependent on the species. As expected, an important difference in the styrene concentration in blood was observed: the solvent concentrations were fourfold higher in the rat than in the guinea pig. Therefore, it is clear that a pharmacokinetic or an uptake difference might explain the difference in susceptibility observed between the two species. Moreover, the metabolism pathways of the solvents were different depending on the species. Attempts to explain differences of vulnerability between the rat and guinea pig are addressed in the present paper.
Assuntos
Cóclea/efeitos dos fármacos , Perda Auditiva Neurossensorial/induzido quimicamente , Estireno/toxicidade , Tolueno/toxicidade , Animais , Audiometria , Cóclea/patologia , Cóclea/fisiopatologia , Relação Dose-Resposta a Droga , Glioxilatos/sangue , Cobaias , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/patologia , Células Ciliadas Auditivas Externas/ultraestrutura , Perda Auditiva Neurossensorial/fisiopatologia , Hipuratos/sangue , Masculino , Ácidos Mandélicos/sangue , Microscopia Eletrônica , Ratos , Ratos Long-Evans , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Estireno/sangue , Estireno/farmacocinética , Tolueno/sangue , Tolueno/farmacocinéticaRESUMO
BACKGROUND: The treatment of late-presenting developmental dislocation of the hip (DDH) is still controversial. A consecutive series of 32 patients not previously treated (43 hips, Tönnis grade 3 or 4) underwent progressive closed reduction followed immediately by innominate osteotomy between 1964 and 1976. They were between 1.5 and 5 years old at the time of pelvic osteotomy. This study was designed to check the outcome of these patients more than 30 years later. METHODS: Eight patients living outside of France (North Africa) could not be reached and one patient had died of an unrelated cause. The remaining 23 patients (32 hips) were reviewed with clinical assessment (Merle d'Aubigné, Harris and Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] scores) and anteroposterior (AP) pelvic radiograph. This represents a 75% rate of follow up at 31 to 44 years post-operatively. RESULTS: In two patients, surgery was repeated due to residual subluxation. Only one patient needed a total hip replacement (THR) 33 years after initial treatment. The Merle d'Aubigné, Harris and WOMAC scores for the surviving hips were excellent or good in almost 80% of the cases. In four cases, radiographic signs "at risk for" osteoarthritis were present. Regularity of the femoral head was perfect in seven hips, regular in 18 and irregular in six. According to the Severin-Seringe classification, 25 hips could be classified as group I (14 group IA and 11 group IB), three group II and three group VII. CONCLUSION: The long-term results of non-previously treated late-presenting DDH by the technique of progressive closed reduction followed by innominate osteotomy are quite good and compare favourably with the long-term results of open reduction with the same osteotomy.
RESUMO
The role of cytochrome P450 activity in the nephrotoxicity of chlorotrifluoroethylene (CTFE) and 1,1-dichloro-2,2-difluoroethylene (DCDFE) was investigated in the male rat. Hepatic cytochrome P450 1A1 and principally P450 2B1/2 were induced by beta-naphthoflavone and phenobarbital, respectively. Nephrotoxicity was evaluated by investigating urine biochemical parameters, kidney histochemistry and histopathological modifications. Both CTFE and DCDFE induce severe nephrotoxicity in rats after 4 h of exposure to 200 and 100 ppm, respectively. Compared with controls, activity levels of gamma-glutamyltranspeptidase (gamma GT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and N-acetyl-beta-D-glucosaminidase (NAG) in 24-h urine were increased similarly, but urinary excretion of glucose, proteins and beta2-microglobulin (beta2-m) and serum urea and creatinine levels were increased. Histopathological and histochemical examinations of kidney sections of CTFE- and DCDFE-exposed rats revealed cellular necrosis and tubular lesions 24 h after exposure. Beta-naphthoflavone-pretreated rats were afforded some protection against the nephrotoxicity of CTFE and DCDFE. Phenobarbital did not modify DCDFE nephrotoxicity but afforded some protection against CTFE nephrotoxicity. In conclusion, CTFE and DCDFE are strong nephrotoxins. Cytochrome P450 1A1 is implicated in CTFE and DCDFE metabolism and one or several cytochromes induced by phenobarbital are implicated in CTFE metabolism. The P450 cytochromes involved in CTFE and DCDFE metabolism probably constitute detoxication metabolic pathways. The nephrotoxicity of CTFE and DCDFE is therefore subordinated to the cytochrome P450 activity involved in their metabolism.
Assuntos
Clorofluorcarbonetos/toxicidade , Sistema Enzimático do Citocromo P-450/metabolismo , Nefropatias/induzido quimicamente , Fenobarbital/farmacologia , beta-Naftoflavona/farmacologia , Animais , Clorofluorcarbonetos/metabolismo , Clorofluorcarbonetos/urina , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Nefropatias/patologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a period of 60 min of nasal exposure to methyl-2-cyanoacrylate, ethyl-2-cyanoacrylate, isopropyl-2-cyanoacrylate and 2-methoxyethyl-2-cyanoacrylate vapors using nose only exposure. Irritation of the upper respiratory tract caused a concentration-dependent decrease in the respiratory rate. The maximum effect occurred within the first 10 min of exposure and was followed by a drop-off in the response during the remainder of the exposure period. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD(50)) was calculated for each chemical. The results show that the four chemicals had similar irritant potencies. The RD(50) values of methyl-2-cyanoacrylate, ethyl-2-cyanoacrylate, isopropyl-2-cyanoacrylate and 2-methoxyethyl-2-cyanoacrylate were 1.4, 0.7, 0.6 and 1.0 p.p.m. Tentative estimates of threshold limit values showed that 0.1 RD(50) was closer to the values recommended by the American Conference of Governmental Industrial Hygienists for methyl- and ethyl-2-cyanoacrylate than 0.03 RD(50). On the basis of a threshold limit value for short-term exposure limit (TLV STEL) equal to 0.1 RD(50), the TLV STELs for the four cyanoacrylates should not exceed 0.1 or 0.2 p.p.m.
Assuntos
Cianoacrilatos/efeitos adversos , Irritantes/efeitos adversos , Concentração Máxima Permitida , Exposição Ocupacional/efeitos adversos , Doenças Respiratórias/complicações , Sensação , Animais , Bioensaio/métodos , Hipersensibilidade/etiologia , Camundongos , Modelos Animais , Testes de Função Respiratória/métodosRESUMO
Nitrogen trichloride (NCl(3)) is an irritant gas released in the air of indoor pools sanitized with chlorine-based disinfectants. In the present study we investigated the effects of NCl(3) on the pulmonary epithelium of pool attendees by measuring the leakage into serum of three lung-specific proteins (pneumoproteins): the alveolar surfactant-associated proteins A and B (SP-A and SP-B) and the bronchiolar 16 kDa Clara cell protein (CC16). These pneumoproteins were measured in the serum of 29 recreational swimmers (16 children and 13 adults) before and after attending a chlorinated pool with a mean NCl(3) concentration of 490 microg m(-3). Pneumoprotein changes in serum were also studied in 14 trained swimmers performing an intensive 45 min standardized swimming session in a chlorinated pool (mean NCl(3) concentration of 355 microg m(-3)) and for the purposes of comparison in a non-chlorinated pool sanitized by the copper/silver method. Serum CC16 was not increased in recreational swimmers, but in trained swimmers serum levels of this protein peaked immediately after strenuous exercise, both in the copper/silver pool and in the chlorinated pool. This acute increase in airway permeability is probably the consequence of the mechanical stress on the epithelial barrier caused by overinflation and/or hyperventilation during intense exercise. Serum levels of SP-A and SP-B were unaffected by strenuous exercise in the copper/silver pool. The two proteins were, however, significantly increased in a time-dependent manner in recreational and trained swimmers attending the chlorinated pool. The intravascular leakage of SP-A and SP-B was already statistically significant after only 1 h of exposure to pool air without exercising and remained elevated for 12 h after. These changes were not associated with decrements in lung function. The ability of NCl(3) to acutely disrupt the lung epithelium barrier was confirmed in mice using serum CC16 and plasma proteins in bronchoalveolar lavage fluid as permeability markers. The significance of these permeability changes induced by NCl(3) in the deep lung is presently unknown. In view of the increasing and widespread human exposure to this gas not only in indoor pools but also in a variety of other situations, these findings warrant further study.