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1.
Toxicol Pathol ; 42(1): 229-42, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24226507

RESUMO

Pancreatic toxicity commonly affects the endocrine or exocrine pancreas. However, it can also occur at the endocrine-exocrine interface (EEI), where the capillary network of the islet merges with the capillaries of the surrounding acinar tissue, that is, the insulo-acinar portal system. The goal of this article is to describe a novel, test article-induced pancreatic toxicity that originated at the EEI and to summarize investigations into the mechanistic basis of the injury. This injury was initially characterized by light microscopy in 7/14 day-toxicity studies in Sprague-Dawley (Crl: CD®[SD]) rats with undisclosed test articles. Microvascular injury at the interface resulted in peri-islet serum exudation, fibrin deposition, hemorrhage, inflammation, and secondary degeneration/necrosis of surrounding exocrine tissue. More chronic injury presented as islet fibrosis and lobular atrophy. Direct cytotoxicity affecting the capillary endothelium at the EEI was confirmed ultrastructurally on day 4. Endothelial microparticle and blood flow studies further confirmed endothelial involvement. Similar lesions occurred less frequently in 2 other rat strains and not in the mouse, dog, or cynomolgus macaque. In summary, in vivo and investigative study data confirmed primary endothelial cytotoxicity in the pathogenesis of this lesion and suggested that the lesion may be rat/rat strain-specific and of uncertain relevance for human safety risk assessment.


Assuntos
Ilhotas Pancreáticas/efeitos dos fármacos , Chumbo/toxicidade , Pâncreas Exócrino/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pancreatite/patologia , Animais , Capilares/efeitos dos fármacos , Capilares/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Hemodinâmica , Hemorragia/induzido quimicamente , Hemorragia/patologia , Ilhotas Pancreáticas/patologia , Masculino , Pâncreas/patologia , Pâncreas Exócrino/patologia , Pancreatite/induzido quimicamente , Sistema Porta/efeitos dos fármacos , Sistema Porta/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Medição de Risco , Testes de Toxicidade Aguda
2.
Curr Protoc Toxicol ; Chapter 14: Unit 14.11, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23408193

RESUMO

Primary hepatocyte sandwich cultures are useful for a variety of research applications where maintenance of metabolic competency is essential. To ensure an optimal hepatocellular phenotype, cells are seeded on collagen-coated dishes and embedded with an overlay of Matrigel. This culturing condition makes gene silencing by traditional reagent-mediated transfection methods challenging. Here, an siRNA delivery method in primary mouse hepatocytes that allows cells to be cultured with Matrigel overlay is described. This method delivers >80% mRNA silencing with minimal alterations in cell viability. A 96-well format allows for high-throughput RNA processing and downstream quantitative PCR applications and reduces time and resources. This format is particularly useful when experiments requiring many different sampling conditions (such as pharmacologic dose-response curves) are required.


Assuntos
Inativação Gênica , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Cultura Primária de Células/métodos , RNA Mensageiro/genética , RNA Interferente Pequeno , Transfecção/métodos , Animais , Células Cultivadas , Camundongos , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
Am J Respir Cell Mol Biol ; 47(1): 120-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22427537

RESUMO

Although obesity is implicated in numerous health complications leading to increased mortality, the relationship between obesity and outcomes for critically ill patients appears paradoxical. Recent studies have reported better outcomes and lower levels of inflammatory cytokines in obese patients with acute lung injury (ALI)/acute respiratory distress syndrome, suggesting that obesity may ameliorate the effects of this disease. We investigated the effects of obesity in leptin-resistant db/db obese and diet-induced obese mice using an inhaled LPS model of ALI. Obesity-associated effects on neutrophil chemoattractant response were examined in bone marrow neutrophils using chemotaxis and adoptive transfer; neutrophil surface levels of chemokine receptor CXCR2 were determined by flow cytometry. Airspace neutrophilia, capillary leak, and plasma IL-6 were all decreased in obese relative to lean mice in established lung injury (24 h). No difference in airspace inflammatory cytokine levels was found between obese and lean mice in both obesity models during the early phase of neutrophil recruitment (2-6 h), but early airspace neutrophilia was reduced in db/db obese mice. Neutrophils from uninjured obese mice demonstrated diminished chemotaxis to the chemokine keratinocyte cytokine compared with lean control mice, and adoptive transfer of obese mouse neutrophils into injured lean mice revealed a defect in airspace migration of these cells. Possibly contributing to this defect, neutrophil CXCR2 expression was significantly lower in obese db/db mice, and a similar but nonsignificant decrease was seen in diet-induced obese mice. ALI is attenuated in obese mice, and this blunted response is in part attributable to an obesity-associated abnormal neutrophil chemoattractant response.


Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Neutrófilos/imunologia , Obesidade/imunologia , Síndrome do Desconforto Respiratório/fisiopatologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Quimiotaxia de Leucócito , Modelos Animais de Doenças , Interleucina-6/sangue , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Infiltração de Neutrófilos , Obesidade/metabolismo , Receptores de Interleucina-8B/biossíntese
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