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1.
Toxicol Pathol ; 42(5): 923-35, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24292388

RESUMO

Chronic administration of drisapersen, a 2'-OMe phosphorothioate antisense oligonucleotide (AON) to mice and monkeys resulted in renal tubular accumulation, with secondary tubular degeneration. Glomerulopathy occurred in both species with species-specific characteristics. Glomerular lesions in mice were characterized by progressive hyaline matrix accumulation, accompanied by the presence of renal amyloid and with subsequent papillary necrosis. Early changes involved glomerular endothelial hypertrophy and degeneration, but the chronic glomerular amyloid and hyaline alterations in mice appeared to be species specific. An immune-mediated mechanism for the glomerular lesions in mice was supported by early inflammatory changes including increased expression of inflammatory cytokines and other immunomodulatory genes within the renal cortex, increased stimulation of CD68 protein, and systemic elevation of monocyte chemotactic protein 1. In contrast, kidneys from monkeys given drisapersen chronically showed less severe glomerular changes characterized by increased mesangial and inflammatory cells, endothelial cell hypertrophy, and subepithelial and membranous electron-dense deposits, with ultrastructural and immunohistochemical characteristics of complement and complement-related fragments. Lesions in monkeys resembled typical features of C3 glomerulopathy, a condition described in man and experimental animals to be linked to dysregulation of the alternative complement pathway. Thus, inflammatory/immune mechanisms appear critical to glomerular injury with species-specific sensitivities for mouse and monkey. The lower observed proinflammatory activity in humans as compared to mice and monkeys may reflect a lower risk of glomerular injury in patients receiving AON therapy.


Assuntos
Inflamação/patologia , Nefropatias/patologia , Glomérulos Renais/efeitos dos fármacos , Oligonucleotídeos Antissenso/efeitos adversos , Animais , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Nefropatias/induzido quimicamente , Glomérulos Renais/patologia , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Oligonucleotídeos Antissenso/administração & dosagem , Medição de Risco , Especificidade da Espécie
2.
Toxicol Pathol ; 39(6): 958-68, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21885873

RESUMO

The purpose of this study was to compare the toxicity of three marketed corticosteroid receptor agonists (mometasone furoate, budesonide, or flunisolide) to the stomach of female CD-1 mice following oral administration via the diet for up to 52 weeks, with a 16-week recovery period (budesonide and flunisolide). A range of tissues was examined by light microscopy, accompanied by clinical pathology measurements to assess anticipated corticosteroid effects as a surrogate marker of systemic drug exposure. Microscopic changes seen in the stomach with each corticosteroid included pyloric hyalinization. This previously unreported finding was investigated using histochemical and immunohistochemical techniques and was found to consist of hyalinized collagen, in association with increased immunohistochemical signal for transglutaminase-2 and osteopontin. The significance of the osteopontin finding is unclear; however, the ability of transglutaminase-2 to facilitate the formation of degradation resistant protein bonds implies this protein may be involved in the pathogenesis of this change. Furthermore, published evidence that transglutaminase-2 may be induced by a corticosteroid agonist raises the possibility that pyloric stomach hyalinization may be a class effect of corticosteroids via the action of this enzyme.


Assuntos
Corticosteroides/agonistas , Anti-Inflamatórios/toxicidade , Budesonida/toxicidade , Fluocinolona Acetonida/análogos & derivados , Hialina/metabolismo , Pregnadienodiois/toxicidade , Piloro/metabolismo , Administração Oral , Corticosteroides/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Budesonida/administração & dosagem , Feminino , Fluocinolona Acetonida/administração & dosagem , Fluocinolona Acetonida/toxicidade , Proteínas de Ligação ao GTP/metabolismo , Camundongos , Camundongos Endogâmicos , Microscopia Eletrônica , Furoato de Mometasona , Osteopontina/metabolismo , Pregnadienodiois/administração & dosagem , Proteína 2 Glutamina gama-Glutamiltransferase , Piloro/anatomia & histologia , Transglutaminases/metabolismo
3.
Toxicol Pathol ; 37(3): 315-23, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19380841

RESUMO

Large eosinophilic cytoplasmic inclusions (ECIs) are occasionally seen in untreated rat Clara cells. Following inhalation exposure to a corticosteroid, the number of ECIs was increased. This is the first histopathological description of rat ECIs and attempted characterization by immunohistochemistry, in situ hybridization, and electron microscopy. ECIs were strongly positive for surfactant protein D (SP-D) and weakly positive for Clara cell specific protein (CCSP). Clara cell cytoplasm was positive for CCSP mRNA regardless of ECIs, but not within ECIs. Corticosteroid treatment and ECI presence did not affect the immunohistochemistry and in situ hybridization staining intensities. Electron microscopy revealed large intracytoplasmic granules with an irregular limiting membrane. The ECI number was microscopically quantified in rats from three-, six-, and twenty-four-month studies. The mean ECI counts in treated rats increased from three- to fifty-four-fold with a positive dose-related trend, when compared with vehicle controls. Although the mechanism is unclear, SP-D and to a lesser extent CCSP accumulate in the ECIs. As human bronchial epithelium does not appear to contain structures analogous to the ECI, it is suggested that the observation of an increased number of ECIs in the treated rats is not likely to be relevant for human clinical risk assessment.


Assuntos
Corticosteroides/farmacologia , Corpos de Inclusão/metabolismo , Exposição por Inalação/efeitos adversos , Uteroglobina/metabolismo , Administração por Inalação , Animais , Relação Dose-Resposta a Droga , Eosinófilos/metabolismo , Eosinófilos/ultraestrutura , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Feminino , Imuno-Histoquímica , Hibridização In Situ , Corpos de Inclusão/ultraestrutura , Masculino , Proteína D Associada a Surfactante Pulmonar/genética , Proteína D Associada a Surfactante Pulmonar/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Uteroglobina/genética , Uteroglobina/ultraestrutura
4.
Toxicol Pathol ; 35(5): 735-40, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17849355

RESUMO

Pulmonary Neuroendocrine Cells (PNEC) are found as clusters called neuroepithelial bodies (NEB) or as single cells scattered in the respiratory epithelium. Pulmonary neuroendocrine cell hyperplasia is recorded in humans and experimentally manipulated rodents. The objectives of this work were to identify the optimal immunohistochemical markers for PNEC in the rat for use on paraffin-embedded, formalin-fixed material and to provide the first comparative incidence of PNEC hyperplasia in untreated 2-year-old rats of different strains. Calcitonin-gene related peptide (CGRP) and protein G product 9.5 (PGP9.5) antibodies identified PNEC consistently and selectively. In contrast, PNEC did not express chromogranin-A or S-100. PNEC hyperplasia was defined as foci of PNEC with greater than 40 nuclei, excluding overlying respiratory epithelium and submucosal PNEC. PNEC hyperplasia was observed at low incidence (0-7%) in untreated 2-year-old Sprague-Dawley, Han Wistar and Wistar rats but not Fischer 344 rats. This is the first report of spontaneous PNEC hyperplasia in rats. The cause of this hyperplasia is unknown, but experimental models that induce PNEC hyperplasia by causing bronchiolar cell injury are discussed. PNEC neoplasia in the rat is unreported in the literature and was not observed in animals examined in this study.


Assuntos
Pulmão/patologia , Sistemas Neurossecretores/patologia , Envelhecimento , Animais , Peptídeo Relacionado com Gene de Calcitonina/análise , Hiperplasia , Imuno-Histoquímica , Incidência , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Ratos Wistar , Ubiquitina Tiolesterase/análise
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