RESUMO
The stochastic effects in the lung of inhaled, insoluble particles of alpha- and beta-emitting particles and low-linear energy transfer (LET) thoracic irradiation were compared in rats using data from previously conducted studies. Male and female F344 rats were exposed briefly by nasal inhalation to relatively insoluble aerosols of CeO(2) or PuO(2) to achieve a range of four lung burdens. The mean lifetime beta doses to the lung were 3.6 + or - 1.3 Gy, 6.8 + or - 1.7 Gy, 12 + or - 4.5 Gy, and 37 + or - 5.9 Gy. The mean lifetime alpha doses to the lung were 0.06 + or - 0.03 Gy, 0.95 + or - 0.46 Gy, 3.7 + or - 1.6 Gy, and 12 + or - 2.4 Gy. Additional rats were exposed to fractionated thoracic doses of x rays given on 10 successive working days. The lifetime doses to the lung were 3.3 Gy, 5.7 Gy, 11 Gy, and 38 Gy. Appropriate sham controls were included in each group and all groups were observed for their life spans. Lung neoplasms were found after all exposures, with the incidence increasing with radiation dose. Rats exposed to PuO(2) had the highest incidence, 94% in the group with a dose of 12 Gy. The incidence in the groups exposed to inhaled CeO(2) or fractionated thoracic x-irradiation was not significantly different. The incidence of lung tumors in the PuO(2) groups was 21 times higher than that of the groups exposed to the lower LET radiations. These results support a radiation-weighting factor of 20, as recommended by ICRP 60.
Assuntos
Aerossóis/toxicidade , Radioisótopos de Cério/toxicidade , Neoplasias Pulmonares/etiologia , Pulmão/efeitos da radiação , Neoplasias Induzidas por Radiação/etiologia , Plutônio/toxicidade , Raios X/efeitos adversos , Administração por Inalação , Aerossóis/administração & dosagem , Aerossóis/química , Partículas alfa , Animais , Partículas beta , Carga Corporal (Radioterapia) , Cério , Relação Dose-Resposta à Radiação , Feminino , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Neoplasias Induzidas por Radiação/patologia , Ratos , Ratos Endogâmicos F344 , Processos EstocásticosRESUMO
Rats were exposed once by inhalation to plutonium-239 dioxide ((239)PuO(2)), resulting in chronic alpha-particle irradiation of the lung, and exposed chronically to cigarette smoke to examine carcinogenic interactions between the two exposures. F344 rats were exposed to (239)PuO(2) to achieve an initial lung burden of 0.5 kBq and then exposed 6 h/day, 5 days/week to cigarette smoke at 100 or 250 mg particulate matter/m(3) for up to 30 months. Exposure to cigarette smoke increased the cumulative radiation dose to lung by slowing the clearance of (239)PuO(2). (239)PuO(2) alone did not affect survival, but the higher cigarette smoke exposure shortened survival in females. Combined exposure to (239)PuO(2) and cigarette smoke acted synergistically to shorten survival in both genders. The combined effects of cigarette smoke and (239)PuO(2) were approximately additive for lung hyperplasia and adenomas but were strongly synergistic for carcinomas. Differences between observed incidences and incidences predicted by survival-adjusted models accounting for increased radiation dose revealed a substantial component of synergy for carcinomas above that attributable to the radiation dose effect. The synergy for malignant lung tumors is consistent with findings from uranium miners and nuclear weapons production workers. These results bolster confidence in the epidemiological findings and have implications for risk assessment.
Assuntos
Cocarcinogênese , Neoplasias Pulmonares/etiologia , Nicotiana , Plutônio/toxicidade , Fumaça , Aerossóis , Animais , Feminino , Exposição por Inalação , Pulmão/patologia , Pulmão/efeitos da radiação , Masculino , Doses de Radiação , Ratos , Ratos Endogâmicos F344RESUMO
The primary target for uranium toxicity is the kidney. The most frequently used guideline for uranium kidney burdens is the International Commission on Radiological Protection value of 3 microg U g(-1) kidney, a value that is based largely upon chronic studies in animals. In the present effort, a risk model equation was developed to assess potential outcomes of acute uranium exposure. Twenty-seven previously published case studies in which workers were acutely exposed to soluble compounds of uranium (as a result of workplace accidents) were analyzed. Kidney burdens of uranium for these individuals were determined based on uranium in the urine, and correlated with health effects observed over a period of up to 38 years. Based upon the severity of health effects, each individual was assigned a score (- to +++) and then placed into a Renal Effects Group (REG). A discriminant analysis was used to build a model equation to predict the REG based on the amount of uranium in the kidneys. The model equation was able to predict the REG with 85% accuracy. The risk model was used to predict the REG for soldiers exposed to depleted uranium as a result of friendly fire incidents during the 1991 Gulf War. This model equation can also be used to predict the REG of new cases in which acute exposures to uranium have occurred.
Assuntos
Aerossóis/análise , Contaminação Radioativa do Ar/estatística & dados numéricos , Armas de Fogo/estatística & dados numéricos , Nefropatias/epidemiologia , Exposição Ocupacional/estatística & dados numéricos , Lesões por Radiação/epidemiologia , Urânio/análise , Algoritmos , Partículas beta , Simulação por Computador , Guerra do Golfo , Humanos , Incidência , Militares , Óxidos/análise , Monitoramento de Radiação/métodos , Resíduos Radioativos/estatística & dados numéricos , Medição de Risco/métodos , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Assessment of the health risk from exposure to aerosols of depleted uranium (DU) is an important outcome of the Capstone aerosol studies that established exposure ranges to personnel in armored combat vehicles perforated by DU munitions. Although the radiation exposure from DU is low, there is concern that DU deposited in the body may increase cancer rates. Radiation doses to various organs of the body resulting from the inhalation of DU aerosols measured in the Capstone studies were calculated using International Commission on Radiological Protection (ICRP) models. Organs and tissues with the highest calculated committed equivalent 50-y doses were lung and extrathoracic tissues (nose and nasal passages, pharynx, larynx, mouth, and thoracic lymph nodes). Doses to the bone surface and kidney were about 5 to 10% of the doses to the extrathoracic tissues. Organ-specific risks were estimated using ICRP and U.S. Environmental Protection Agency (EPA) methodologies. Risks for crewmembers and first responders were determined for selected scenarios based on the time interval of exposure and for vehicle and armor type. The lung was the organ with the highest cancer mortality risk, accounting for about 97% of the risks summed from all organs. The highest mean lifetime risk for lung cancer for the scenario with the longest exposure time interval (2 h) was 0.42%. This risk is low compared with the natural or background risk of 7.35%. These risks can be significantly reduced by using an existing ventilation system (if operable) and by reducing personnel time in the vehicle immediately after perforation.
Assuntos
Aerossóis/análise , Contaminação Radioativa do Ar/estatística & dados numéricos , Armas de Fogo/estatística & dados numéricos , Militares/estatística & dados numéricos , Neoplasias Induzidas por Radiação/epidemiologia , Exposição Ocupacional/estatística & dados numéricos , Lesões por Radiação/epidemiologia , Urânio/análise , Algoritmos , Partículas beta , Simulação por Computador , Guerra do Golfo , Humanos , Incidência , Monitoramento de Radiação/métodos , Resíduos Radioativos/estatística & dados numéricos , Medição de Risco/métodos , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Peroxisome proliferator-activated receptors (PPAR) are involved in the pathogenesis of insulin resistance, diabetes, hyperlipidemias, and related complications. Consequently, a mechanistic understanding of PPAR subtypes and their activation provides promising therapeutic targets for the management of type 2 diabetes mellitus and the metabolic syndrome. Available data from rodent carcinogenicity studies, however, demonstrate that PPAR agonists can be tumorigenic in one or more species of rodents at multiple sites. Sufficient data are not yet available to explain the mode(s) of action for most of these tumor types. There has been information presented by FDA that indicates there are urothelial changes in the monkey (and possibly the dog) in addition to the rat. Outstanding questions exist regarding potency, species differences, safety margins, and other issues. In 2005, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) PPAR Agonist Project Committee was established to advance research on the modes of action and potential human relevance of emerging rodent tumor data. Additionally, the HESI PPAR Agonist Project Committee authorized a Pathology Working Group (PWG) to examine the urinary bladder from cynomolgus monkeys. The focus of this PWG was to establish consistent diagnostic criteria for urothelial changes and to assess the potential relationship of these changes to treatment. Specific diagnostic criteria and nomenclature were recommended for the diagnosis of urothelial granules, vacuolation, hypertrophy, and hyperplasia in studies conducted with PPARgamma and dual alpha/gamma agonists in cynomolgus monkeys, which will assist investigators performing toxicity studies to provide data in a consistent manner between studies and laboratories. In this review of selected tissues, treatment with PPAR agonists was not associated with urothelial hypertrophy or hyperplasia, but there was an increased incidence in the size and frequency of vacuoles within the superficial urothelial and adjacent intermediate cell layers.
Assuntos
PPAR alfa/agonistas , PPAR gama/agonistas , Bexiga Urinária/patologia , Urotélio/patologia , Animais , Grânulos Citoplasmáticos/efeitos dos fármacos , Grânulos Citoplasmáticos/patologia , Feminino , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Hipertrofia/induzido quimicamente , Hipertrofia/patologia , Imuno-Histoquímica , Macaca fascicularis , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/fisiologia , Bexiga Urinária/efeitos dos fármacos , Urotélio/efeitos dos fármacos , Vacúolos/efeitos dos fármacos , Vacúolos/patologiaRESUMO
Leukocytes contain both nicotinic and muscarinic receptors, and while activation of nicotinic receptors suppresses immune/inflammatory responses, the role of muscarinic receptors in immunity is unclear. We examined the effects of a muscarinic receptor antagonist (atropine) and agonist (oxotremorine), administered chronically through miniosmotic pumps, on immune/inflammatory responses in the rat. Results show that while oxotremorine stimulated, atropine inhibited the antibody and T-cell proliferative responses. Moreover, atropine also suppressed the turpentine-induced leukocytic infiltration and tissue injury, and inhibited chemotaxis of leukocytes toward neutrophil and monocyte/lymphocyte chemoattractants. Thus, activation of nicotinic and muscarinic receptors has opposite effects on the immune/inflammatory responses.
Assuntos
Formação de Anticorpos/fisiologia , Atropina/farmacologia , Inflamação/fisiopatologia , Ativação Linfocitária/fisiologia , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Oxotremorina/farmacologia , Receptores Muscarínicos/fisiologia , Linfócitos T/imunologia , Abscesso/induzido quimicamente , Abscesso/imunologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Quimiocina CCL2/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos Lew , Receptores Muscarínicos/efeitos dos fármacos , Receptores Nicotínicos/fisiologia , Organismos Livres de Patógenos Específicos , Linfócitos T/efeitos dos fármacos , Terebintina/toxicidadeRESUMO
Beagle dogs inhaled graded exposure levels of insoluble plutonium dioxide ((239)PuO(2)) aerosols in one of three monodisperse particle sizes at the Lovelace Respiratory Research Institute (LRRI) to study the life-span health effects of different degrees of alpha-particle dose non-uniformity in the lung. The primary noncarcinogenic effects seen were lymphopenia, atrophy and fibrosis of the thoracic lymph nodes, and radiation pneumonitis and pulmonary fibrosis. Radiation pneumonitis/ pulmonary fibrosis occurred from 105 days to more than 11 years after exposure, with the lowest associated alpha-particle dose being 5.9 Gy. The primary carcinogenic effects also occurred almost exclusively in the lung because of the short range of the alpha-particle emissions. The earliest lung cancer was observed at 1086 days after the inhalation exposure. The most common type seen was papillary adenocarcinoma followed by bronchioloalveolar carcinoma. These lung cancer results indicate that a more uniform distribution of alpha-particle dose within the lung has an equal or possibly greater risk of neoplasia than less uniform distributions of alpha-particle dose. The results are consistent with a linear relationship between dose and response, but these data do not directly address the response expected at low dose levels. No primary tumors were found in the tracheobronchial and mediastinal lymph nodes despite the high alpha-particle radiation doses to these lymph nodes, and no cases of leukemia were observed.
Assuntos
Exposição por Inalação , Plutônio/toxicidade , Absorção , Animais , Cães , Relação Dose-Resposta à Radiação , Feminino , Hematologia , Neoplasias Pulmonares/etiologia , Masculino , Tamanho da Partícula , Plutônio/administração & dosagem , Plutônio/química , Plutônio/farmacocinética , Fibrose Pulmonar/etiologia , Doses de Radiação , Pneumonite por Radiação/etiologia , Radiometria , Medição de Risco , Distribuição TecidualRESUMO
In the past several years an increased number of lung tumors has been reported in laboratory studies of rats and mice after lifetime exposure to mainstream cigarette smoke. Proliferative epithelial lesions are present in the lungs of both species and are apparent antecedent lesions to benign and malignant tumors. Both species have alveolar epithelia hyperplasia, alveolar adenomas, and alveolar carcinomas. The incidence of all three are more in the rats. In addition, mice also have bronchiolar epithelial hyperplasia and bronchial papillomas not found in rats. Rats have a low incidence of squamous cyst that is not found in mice. Lung tumors in rats and mice are found at the end of the life span and rarely metastasize. The characteristics of the lung tumors, and the proliferative changes associated with the tumors, are important in helping understand the mechanisms of lung cancer induction. These studies in rats and mice allow new approaches to the study of cigarette smoke-induced changes in the lung.
Assuntos
Adenocarcinoma/etiologia , Adenoma/etiologia , Neoplasias Pulmonares/etiologia , Lesões Pré-Cancerosas/etiologia , Alvéolos Pulmonares/efeitos dos fármacos , Fumar/efeitos adversos , Adenocarcinoma/patologia , Adenoma/patologia , Administração por Inalação , Animais , Brônquios/efeitos dos fármacos , Brônquios/patologia , Neoplasias Brônquicas/etiologia , Neoplasias Brônquicas/patologia , Modelos Animais de Doenças , Feminino , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Papiloma/etiologia , Papiloma/patologia , Lesões Pré-Cancerosas/patologia , Alvéolos Pulmonares/patologia , Ratos , Ratos Endogâmicos F344 , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Especificidade da EspécieRESUMO
The prophylactic use of zidovudine (3'-azido-3'-deoxythymidine, AZT) during pregnancy greatly reduces transmission of HIV-1 from infected mothers to their infants; however, the affinity of host cell DNA polymerases for AZT also allows for its incorporation into host cell DNA, predisposing to cancer development. To expand upon previous transplacental carcinogenesis assays performed in CD-1 mice, the transplacental carcinogenicity of AZT was evaluated in a second mouse strain and a second rodent species. Date-mated female mice and rats were gavaged daily with 0, 80, 240, or 480 mg AZT/kg bw during the last 7 days of gestation. At 2 years postpartum, male and female B6C3F1 mouse and F344 rat offspring (n = 44-46 of each sex and species/treatment group) were necropsied for gross and microscopic tissue examinations. Under the conditions of these two-year studies, there was clear evidence of carcinogenic activity based upon significant dose-related trends and increases in the incidences of hemangiosarcoma in male mice and mononuclear cell leukemia in female rats. There was some evidence of carcinogenic activity in the livers of male mice based upon a positive trend and an increased incidence of hepatic carcinoma in the high-dose AZT group. The incidence of gliomas in female rats exceeded the historical background rates for gliomas in F344 rats. P53 overexpression was detected in some AZT-treated mouse neoplasms. These and other cancer-related findings confirm and extend those of previous transplacental carcinogenicity studies of AZT in mice, support the need for long-term follow-up of nucleoside reverse transcriptase inhibitor (NRTI)-exposed children, and indicate the necessity for effective protective strategies against NRTI-induced side effects.
Assuntos
Fármacos Anti-HIV/toxicidade , Carcinógenos/toxicidade , Neoplasias/induzido quimicamente , Inibidores da Transcriptase Reversa/toxicidade , Zidovudina/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Masculino , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos , Neoplasias/metabolismo , Neoplasias/patologia , Gravidez , Ratos , Ratos Endogâmicos F344 , Proteína Supressora de Tumor p53/metabolismoRESUMO
Toxicologic pathologists need to understand the comparative oncology of lung tumors because lung cancer is a common and serious cancer in the human population. Lung cancer in humans is known to be caused by cigarette smoke and a number of other carcinogens in the environment. Animal studies are needed to elucidate possible interactions with other potential carcinogens in environmental or occupational settings. In addition, knowledge of dose-response relationships and potential synergistic effects are needed to minimize harmful effects. Understanding the pathogenesis of common lung tumors will also aid in the prevention, diagnosis and treatment of the disease. Toxicologic pathologists need to remember several important points about lung tumors. The lung cancer response varies among species. Important factors in this variation are the nature of the administered carcinogen, the tissue dose of the carcinogen, the mode of exposure, the sensitivity of the test animal species and the similarity to the human response. Studies of molecular changes are important new tools to understanding lung carcinogenesis. For example, the molecular changes in lung tumors of mice and humans have a number of similarities that may be important in evaluating the significance of compound-induced lung tumors in mice.
Assuntos
Modelos Animais de Doenças , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Animais , Carcinógenos/toxicidade , Cocarcinogênese , Predisposição Genética para Doença , Humanos , Camundongos , Mutação , Ratos , Especificidade da EspécieRESUMO
Environmental factors play a major role in a majority of lung diseases. Asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and many interstitial lung diseases are influenced or caused by environmental factors. Animals and humans may respond differently to the same agent, and a study of the comparative pathology between the two is useful for optimizing animal models of environmental lung disease and for evaluating their predictive value in carcinogenicity studies. This overview describes the most common nonneoplastic pathologic pulmonary responses to inhaled environmental agents in the human and contrasts them with the responses observed in rats exposed to the same agents. We show both similarities and difference in response to the same agents; furthermore, both species have unique responses to some agents (for example, progressive massive fibrosis in the human and proliferative squamous lesions in the rat). Quantitative analysis of the grades of response to three environmental particulate dusts revealed differences between the 2 species at the cellular level. Specifically, acute intra-alveolar inflammation, alveolar epithelial hyperplasia, and alveolar lipoproteinosis were all greater in rats than in humans exposed to the same agents. These differences may account for differences between the 2 species in carcinogenic response to nonfibrous particulates.
Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Exposição Ocupacional/efeitos adversos , Pneumoconiose/etiologia , Pneumoconiose/patologia , Animais , Carvão Mineral , Modelos Animais de Doenças , Humanos , Ratos , Dióxido de Silício , Especificidade da Espécie , TalcoRESUMO
Small increases in concentrations of ambient particulate matter (PM*) have been linked to adverse health effects, especially in older people and people with preexisting respiratory disease. Some epidemiologic studies have shown the association to be stronger with PM less than 2.5 microm in aerodynamic diameter (PM2.5) than with PM less than 10 microm in aerodynamic diameter (PM10). Some scientists and regulators suggest that 2.5 microm might be an arbitrary cutoff and that the effects might be more pronounced for PM less than 0.1 microm in aerodynamic diameter (ultrafine PM). Our first aim was to determine the relation between size of respirable particles and particle toxicity, as well as the health effects of short-term increases (spikes) in particle concentration against backgrounds of relatively low or high baseline exposures. Our second aim was to determine the effect of spikes in concentration of fine particles (0.7 microm in mass median aerodynamic diameter [MMAD]) and ultrafine particles (35 nm in count median diameter [CMD]) of disparate composition: vanadium pentoxide (V2O5) and carbon black. The relative toxicity of these particles was determined in aged rats with mild pulmonary inflammation induced by instilled endotoxin. Our third aim was to determine the influence of age (aged vs young adult) on particle-induced toxicity in these rats.
Assuntos
Carbono/efeitos adversos , Exposição por Inalação/análise , Compostos de Vanádio/efeitos adversos , Fatores Etários , Animais , Carbono/administração & dosagem , Masculino , New Mexico , Tamanho da Partícula , Pneumonia/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Compostos de Vanádio/administração & dosagemRESUMO
Epidemiological studies have implicated wood smoke as a risk factor for exacerbating asthma. However, comparisons of findings in animal models with those in humans are currently not possible, because detailed clinically relevant measurements of pulmonary function are not available in animal studies. Brown Norway rats were immunized with ovalbumin and exposed to either filtered air or wood smoke at 1 mg particulate matter/m(3) for 70 days and challenged with allergen during the last 4 days of exposure. Baseline values for dynamic lung compliance were lower while functional residual capacity was increased in rats exposed to wood smoke compared to rats exposed to filtered air. IFN-gamma levels were reduced and IL-4 levels increased in the bronchoalveolar lavage fluid and blood plasma, inflammatory lesions in the lungs were 21% greater, and airway mucous cells/mm basal lamina were non-significantly increased in rats exposed to wood smoke compared to controls. Collectively, these studies suggest that the pulmonary function was affected in rats by exposure to wood smoke and this decline was associated with only minor increases in inflammation of the lung. Therefore, this animal model may be useful to elucidate the mechanisms of the decline in pulmonary function caused by environmental pollutants when asthmatics are exposed to allergen.
Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Hipersensibilidade Respiratória/induzido quimicamente , Fumaça/efeitos adversos , Madeira , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Alérgenos/farmacologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Exposição por Inalação , Interferon gama/análise , Interleucina-4/análise , Masculino , Ovalbumina/farmacologia , Ratos , Ratos Endogâmicos BN , Testes de Função Respiratória , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Fumaça/análiseRESUMO
Although cigarette smoke has been epidemiologically associated with lung cancer in humans for many years, animal models of cigarette smoke-induced lung cancer have been lacking. This study demonstrated that life time whole body exposures of female B6C3F1 mice to mainstream cigarette smoke at 250 mg total particulate matter/m(3) for 6 h per day, 5 days a week induces marked increases in the incidence of focal alveolar hyperplasias, pulmonary adenomas, papillomas and adenocarcinomas. Cigarette smoke-exposed mice (n = 330) had a 10-fold increase in the incidence of hyperplastic lesions, and a 4.6-fold (adenomas and papillomas), 7.25-fold (adenocarcinomas) and 5-fold (metastatic pulmonary adenocarcinomas) increase in primary lung neoplasms compared with sham-exposed mice (n = 326). Activating point mutations in codon 12 of the K-ras gene were identified at a similar rate in tumors from sham-exposed mice (47%) and cigarette smoke-exposed mice (60%). The percentages of transversion and transition mutations were similar in both the groups. Hypermethylation of the death associated protein (DAP)-kinase and retinoic acid receptor (RAR)-beta gene promoters was detected in tumors from both sham- and cigarette smoke-exposed mice, with a tendency towards increased frequency of RAR-beta methylation in the tumors from the cigarette smoke-exposed mice. These results emphasize the importance of the activation of K-ras and silencing of DAP-kinase and RAR-beta in lung cancer development, and confirm the relevance of this mouse model for studying lung tumorigenesis.
Assuntos
Metilação de DNA , Inativação Gênica/efeitos dos fármacos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Pulmão/efeitos dos fármacos , Fumar/efeitos adversos , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/genética , Adenocarcinoma/secundário , Adenoma/induzido quimicamente , Adenoma/genética , Adenoma/patologia , Administração por Inalação , Animais , Proteínas Reguladoras de Apoptose , Peso Corporal , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Proliferação de Células/efeitos dos fármacos , Proteínas Quinases Associadas com Morte Celular , Feminino , Genes ras/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Hiperplasia/genética , Hiperplasia/patologia , Incidência , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos , Tamanho do Órgão , Papiloma/induzido quimicamente , Papiloma/genética , Papiloma/patologia , Mutação Puntual , Regiões Promotoras Genéticas , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Receptores do Ácido Retinoico/genética , Taxa de SobrevidaRESUMO
Brevetoxins are potent neurotoxins produced by the marine dinoflagellate Karenia brevis. Exposure to brevetoxins may occur during a K. brevis red tide when the compounds become aerosolized by wind and surf. This study assessed possible adverse health effects associated with inhalation exposure to brevetoxin 3, one of the major brevetoxins produced by K. brevis and present in aerosols collected along beaches affected by red tide. Male F344 rats were exposed to brevetoxin 3 at 0, 37, and 237 microg/m3 by nose-only inhalation 2 hr/day, 5 days/week for up to 22 exposure days. Estimated deposited brevetoxin 3 doses were 0.9 and 5.8 microg/kg/day for the low- and high-dose groups, respectively. Body weights of the high-dose group were significantly below control values. There were no clinical signs of toxicity. Terminal body weights of both low- and high-dose-group rats were significantly below control values. Minimal alveolar macrophage hyperplasia was observed in three of six and six of six of the low- and high-dose groups, respectively. No histopathologic lesions were observed in the nose, brain, liver, or bone marrow of any group. Reticulocyte numbers in whole blood were significantly increased in the high-dose group, and mean corpuscular volume showed a significant decreasing trend with increasing exposure concentration. Humoral-mediated immunity was suppressed in brevetoxin-exposed rats as indicated by significant reduction in splenic plaque-forming cells in both low- and high-dose-group rats compared with controls. Results indicate that the immune system is the primary target for toxicity in rats after repeated inhalation exposure to relatively high concentrations of brevetoxins.
Assuntos
Formação de Anticorpos/efeitos dos fármacos , Dinoflagellida/patogenicidade , Exposição por Inalação , Toxinas Marinhas/toxicidade , Oxocinas/toxicidade , Aerossóis , Animais , Peso Corporal , Eutrofização , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
Epidemiological data suggest an association between smoking, respiratory infections, and impaired wound healing. Inflammation is critical in the body's defense against pathogens and in the wound-healing process. Although nicotine is used to treat some inflammatory conditions, the mechanism of this action is largely unknown. To determine how nicotine affects inflammation, rats and mice were exposed to nicotine via miniosmotic pumps, and the inflammatory response to turpentine or influenza virus was assessed. Results showed that while nicotine suppressed the migration of leukocytes to the inflammation/infection site, it increased the influenza titer in the lung. The decreased inflammation correlated with lower chemotaxis/chemokinesis of peripheral blood mononuclear cells (PBMC) toward formyl-methionyl-leucyl-phenylalanine and monocyte chemoattractant protein-1 without affecting the density of their respective receptors. However, nicotine suppressed the chemokine-induced Ca(2+) response in PBMC, indicating impaired chemokine signaling. Thus, because nicotine suppresses leukocyte migration, it might contribute to the delayed wound healing and increased incidence of respiratory infections among smokers.
Assuntos
Inflamação/patologia , Inflamação/prevenção & controle , Nicotina/administração & dosagem , Nicotina/farmacologia , Infecções por Orthomyxoviridae/induzido quimicamente , Infecções por Orthomyxoviridae/patologia , Animais , Cálcio/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Inflamação/genética , Inflamação/metabolismo , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/genética , Vírus da Influenza A/fisiologia , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Ratos , Fumar/efeitos adversos , Terebintina/farmacologia , Carga Viral , Cicatrização/efeitos dos fármacosRESUMO
Cardiac toxicity has been associated with HIV infection and exposure to nucleoside reverse transcriptase inhibitors (NRTIs), but the role of the latter in the development of cardiac disease of HIV-infected patients is uncertain. To investigate the cardiotoxicity of transplacentally administered zidovudine (AZT) or AZT plus lamivudine (3TC) in the absence of HIV infection, we evaluated several biomarkers of cardiac mitochondrial structure and cardiac structure and function in a B6C3F1 mouse model. In utero exposure to AZT-3TC resulted in ultrastructural pathology, loss of mitochondria, and altered echocardiographic measurements in newborn mice. Cardiac pathology and dysfunction persisted into the adult life of female mice exposed in utero to AZT, as evidenced by significant dose-dependent heart enlargement, clusters of atypical mitochondria and myofibril alterations, significantly increased cytochrome c oxidase activity, and significantly higher numbers of mutations in mitochondrial tRNA genes compared with unexposed controls at 18 to 24 mo of age. These data led to the hypothesis that the long-term pathology of peri-natal exposure to these NRTIs is related to persistent mitochondrial DNA mutations in cardiac tissue; that is, the primary damage during drug treatment is mutational (as opposed to affecting polymerase gamma and/or other mitochondrial elements) and leads over time to delayed, progressive cardiotoxicity.
Assuntos
Fármacos Anti-HIV/toxicidade , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/embriologia , Troca Materno-Fetal , Mitocôndrias Cardíacas/efeitos dos fármacos , Zidovudina/toxicidade , Fatores Etários , Animais , Animais Recém-Nascidos , Fármacos Anti-HIV/administração & dosagem , Peso Corporal/efeitos dos fármacos , Cardiomiopatias/patologia , DNA Mitocondrial/genética , Interações Medicamentosas , Eletrocardiografia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Lamivudina/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/ultraestrutura , Mutação , Miocárdio/patologia , Miocárdio/ultraestrutura , Tamanho do Órgão/efeitos dos fármacos , Projetos Piloto , Gravidez , Fatores Sexuais , Zidovudina/administração & dosagem , Zidovudina/farmacocinéticaRESUMO
An animal model of lung carcinogenicity induced by chronic inhalation of mainstream cigarette smoke would be useful for research on carcinogenic mechanisms, smoke composition-response relationships, co-carcinogenicity, and chemoprevention. A study was conducted to determine if chronic whole-body exposures of rats would significantly increase lung tumor incidence. Male and female F344 rats (n = 81 to 178/gender) were exposed whole-body 6 h/day, 5 days/week for up to 30 months to smoke from 1R3 research cigarettes diluted to 100 (LS) or 250 (HS) mg total particulate matter/m(3), or sham-exposed to clean air (C). Gross respiratory tract lesions and standard lung and nasal sections were evaluated by light microscopy. A slight reduction of survival suggested that the HS level was at the maximum tolerated dose as commonly defined. Cigarette smoke exposure significantly increased the incidences of non-neoplastic and neoplastic proliferative lung lesions in females, while nonsignificant increases were observed in males. The combined incidence of bronchioloalveolar adenomas and carcinomas in females were: HS = 14%; LS = 6%; and C = 0%. These incidences represented minima because only standard lung sections and gross lesions were evaluated. Mutations in codon 12 of the K-ras gene occurred in 4 of 23 (17%) tumors. Three mutations were G to A transitions and one was a G to T transversion. The incidence of neoplasia of the nasal cavity was significantly increased at the HS, but not the LS level in both males and females (HS = 6%, LS = 0.3%, C = 0.4% for combined genders). These results demonstrate that chronic whole-body exposure of rats to cigarette smoke can induce lung cancer.
Assuntos
Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Neoplasias Nasais/induzido quimicamente , Neoplasias Nasais/patologia , Fumaça/análise , Fumar/patologia , Administração por Inalação , Animais , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doença Crônica , Códon/genética , Relação Dose-Resposta a Droga , Feminino , Genes ras/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/patologia , Neoplasias Pulmonares/epidemiologia , Masculino , Muco/metabolismo , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/enzimologia , Mucosa Nasal/patologia , Neoplasias Nasais/epidemiologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Análise de SobrevidaRESUMO
Inhalation of crystalline silica may lead to acute or chronic silicosis. Although chronic silicosis is associated with increased incidence/exacerbation of autoimmune disorders, the immunologic effects of chronic silicosis are not completely understood. In an animal model of chronic silicosis, Lewis rats were exposed to filtered air or silica (1.75 microm average particle size) at an exposure concentration of 6.2 mg/m(3), 6 h/d, 5 d/wk for 6 wk, and observed up to 27 wk after the exposure. Based on silica burden, lung histopathology, and immunologic changes, two distinct stages were identified in the development of chronic silicosis. Stage 1 (4-28 d after exposure) was characterized by silica deposition in various tissues, and augmented antibody and cellular immunity. Although bronchoalveolar lavage contained an increased number of activated macrophages, protein and lactate dehydrogenase levels were comparable to controls. In Stage 2 (>/= 10 wk), silica was localized in epithelioid macrophages, and T cell immunity had returned to normal, but the lavage fluids contained increased protein concentration and lactate dehydrogenase activity. Moreover, lungs from silica-treated animals contained neutrophils and lymphocytes, and exhibited granulomatous changes around the silica-containing epithelioid macrophages. Thus, in the early stages of silicosis, silica activates the immune system; however, the progression of lung granulomas does not depend on a continually activated adaptive immune system.
Assuntos
Dióxido de Silício/imunologia , Dióxido de Silício/metabolismo , Silicose/imunologia , Animais , Química Encefálica , Líquido da Lavagem Broncoalveolar/química , Modelos Animais de Doenças , Sistema Imunitário/fisiologia , Pulmão/citologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Tamanho da Partícula , Ratos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Dióxido de Silício/química , Silicose/metabolismo , Silicose/patologia , Baço/química , Baço/citologia , Baço/metabolismoRESUMO
In this study, we determined the carcinogenicity of depleted uranium (DU) metal fragments containing 0.75% titanium in muscle tissues of rats. The results have important implications for the medical management of Gulf War veterans who were wounded with DU fragments and who retain fragments in their soft tissues. We compared the tissue reactions in rats to the carcinogenicity of a tantalum metal (Ta), as a negative foreign-body control, and to a colloidal suspension of radioactive thorium dioxide ((232)Th), Thorotrast, as a positive radioactive control. DU was surgically implanted in the thigh muscles of male Wistar rats as four squares (2.5 x 2.5 x 1.5 mm or 5.0 x 5.0 x 1.5 mm) or four pellets (2.0 x 1.0 mm diameter) per rat. Ta was similarly implanted as four squares (5.0 x 5.0 x 1.1 mm) per rat. Thorotrast was injected at two sites in the thigh muscles of each rat. Control rats had only a surgical implantation procedure. Each treatment group included 50 rats. A connective tissue capsule formed around the metal implants, but not around the Thorotrast. Radiographs demonstrated corrosion of the DU implants shortly after implantation. At later times, rarifactions in the radiographic profiles correlated with proliferative tissue responses. After lifetime observation, the incidence of soft tissue sarcomas increased significantly around the 5.0 x 5.0 mm squares of DU and the positive control, Thorotrast. A slightly increased incidence occurred in rats implanted with the 2.5 x 2.5 mm DU squares and with 5.0 x 5.0 mm squares of Ta. No tumors were seen in rats with 2.0 x 1.0 mm diameter DU pellets or in the surgical controls. These results indicate that DU fragments of sufficient size cause localized proliferative reactions and soft tissue sarcomas that can be detected with radiography in the muscles of rats.