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1.
Comp Med ; 71(3): 240-246, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082856

RESUMO

Ischemic myocardial disease is a major cause of death among humans worldwide; it results in scarring and pallor of the myocardium and triggers an inflammatory response that contributes to impaired left ventricular function. This response includes and is evidenced by the production of several inflammatory cytokines including TNFα, IL1ß, IL4, IFNγ, IL10 and IL6. In the current study, myocardial infarcts were induced in 6 mo old male castrated sheep by ligation of the left circumflex obtuse marginal arteries (OM 1 and 2). MRI was used to measure parameters of left ventricular function that include EDV, ESV, EF, SVI, dp/dt max and dp/dt min at baseline and at 4 wk and 3 mo after infarct induction. We also measured serum concentrations of an array of cytokines. Postmortem histologic findings corroborate the existence of left ventricular myocardial injury and deterioration. Our data show a correlation between serum cytokine concentrations and the development of myocardial damage and left ventricular functional compromise.


Assuntos
Infarto do Miocárdio , Carneiro Doméstico , Animais , Ventrículos do Coração , Masculino , Infarto do Miocárdio/veterinária , Miocárdio , Ovinos , Função Ventricular Esquerda
2.
Front Immunol ; 12: 637630, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717186

RESUMO

Background: Inflammatory bowel disease (IBD) involves an increase in T effector cells in the intestines that disrupts the normal balance with T regulatory cells (Tregs). A therapy that restores this balance has the potential to treat IBD. We have shown that epicutaneous exposure to OVA induces Tregs that are able to induce tolerance. The Tregs also migrate to the intestines where they alleviate colitis in mice, demonstrating the potential for skin induced Tregs to treat intestinal inflammation. We investigated the role of Foxp3, IL-10, and TGF-ß in the suppression of colitis by epicutaneous immunotherapy (ET). Methods: RAG1-/- mice were transferred with CD4+CD45RBhi T cells from wild type mice to induce colitis. To determine whether Foxp3+ Tregs, IL-10-, or TGF-ß-producing Tregs were necessary, Foxp3-DTR, IL-10-/-, or CD4-dnTGFBRII mice were immunized with OVA and OVA TCR enriched T cells were added. As control groups, some mice were given OVA TCR enriched T cells from wild type mice or no OVA TCR enriched T cells. Half of the mice in each group were then exposed on the skin to Viaskin patches containing OVA weekly for 3 weeks. Mice given OVA TCR enriched T cells from Foxp3-DTR mice were given diphtheria toxin (DT) or not in addition to ET. Mice were assessed for weight loss, colon length, colonic cytokine production, and histological inflammation. Results: ET, after injection with OVA TCR enriched T cells derived from wild type mice, prevented weight loss, decreased colonic inflammatory cytokine production and histological colitis. ET in the absence of the OVA TCR enriched T cells did not alleviate colitis. ET, after injection with OVA TCR enriched T cells derived from Foxp3-DTR mice, prevented weight loss, decreased colonic inflammatory cytokine production, and histological colitis. Ablation with DT did not impair the ability of ET to alleviate colitis. ET failed to alleviate colitis when OVA TCR enriched T cells were derived from IL-10-/- or CD4-dnTGFBRII mice. Conclusions: ET through induction of Tregs, which produce IL-10 and TGF-ß, could be a promising treatment for IBD.


Assuntos
Colite/terapia , Imunoterapia Adotiva/métodos , Interleucina-10/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Fator de Crescimento Transformador beta1/metabolismo , Animais , Colite/imunologia , Colite/patologia , Toxina Diftérica/imunologia , Fatores de Transcrição Forkhead/metabolismo , Inflamação/patologia , Inflamação/terapia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Interleucina-10/genética , Intestinos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/imunologia
3.
Emerg Microbes Infect ; 9(1): 2433-2445, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33073694

RESUMO

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide pandemic with high morbidity and mortality. Development of animal models that recapitulate important aspects of coronavirus disease 2019 (COVID-19) is critical for the evaluation of vaccines and antivirals, and understanding disease pathogenesis. SARS-CoV-2 has been shown to use the same entry receptor as SARS-CoV-1, human angiotensin-converting enzyme 2 (hACE2) [1-3]. Due to amino acid differences between murine and hACE2, inbred mouse strains fail to support high titer viral replication of SARS-CoV-2 virus. Therefore, a number of transgenic and knock-in mouse models, as well as viral vector-mediated hACE2 delivery systems have been developed. Here we compared the K18-hACE2 transgenic model to adenovirus-mediated delivery of hACE2 to the mouse lung. We show that K18-hACE2 mice replicate virus to high titers in the nasal turbinates, lung and brain, with high lethality, and cytokine/chemokine production. In contrast, adenovirus-mediated delivery results in viral replication to lower titers limited to the nasal turbinates and lung, and no clinical signs of infection. The K18-hACE2 model provides a stringent model for testing vaccines and antivirals, whereas the adenovirus delivery system has the flexibility to be used across multiple genetic backgrounds and modified mouse strains.


Assuntos
Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/patologia , Peptidil Dipeptidase A/genética , Pneumonia Viral/patologia , Vírus da SARS/crescimento & desenvolvimento , Replicação Viral/genética , Células A549 , Adenoviridae/genética , Enzima de Conversão de Angiotensina 2 , Animais , Betacoronavirus/metabolismo , COVID-19 , Linhagem Celular , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pandemias , Vírus da SARS/metabolismo , SARS-CoV-2 , Células Vero , Ligação Viral
4.
bioRxiv ; 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32676603

RESUMO

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide pandemic with high morbidity and mortality. Development of animal models that recapitulate important aspects of coronavirus disease 2019 (COVID-19) is critical for the evaluation of vaccines and antivirals, and understanding disease pathogenesis. SARS-CoV-2 has been shown to use the same entry receptor as SARS-CoV-1, human angiotensin-converting enzyme 2 (hACE2)(1-3). Due to amino acid differences between murine and hACE2, inbred mouse strains fail to support high titer viral replication of SARS-CoV-2 virus. Therefore, a number of transgenic and knock-in mouse models, as well as viral vector-mediated hACE2 delivery systems have been developed. Here we compared the K18-hACE2 transgenic model to adenovirus-mediated delivery of hACE2 to the mouse lung. We show that K18-hACE2 mice replicate virus to high titers in both the lung and brain leading to lethality. In contrast, adenovirus-mediated delivery results in viral replication to lower titers limited to the lung, and no clinical signs of infection with a challenge dose of 10 4 plaque forming units. The K18-hACE2 model provides a stringent model for testing the ability of vaccines and antivirals to protect against disease, whereas the adenovirus delivery system has the flexibility to be used across multiple genetic backgrounds and modified mouse strains.

5.
Comp Med ; 68(3): 215-220, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29747722

RESUMO

In humans, cardiovascular disease (CVD) is the most frequent cause of death worldwide. Myocardial infarction (MI) is a leading cause of heart failure due to myocardial impairment, yet the progression of the resultant dysfunction is often undetected after incidental or induced myocardial infarction. In this study we tracked the progression of left-sided heart failure in 6-mo-old male castrated sheep in which we created 2 models of myocardial infarction, small and large. Myocardial infarction was induced through ligation of a single branch (obtuse marginal [OM] 1) of the left circumflex coronary artery to create small (mild) infarcts and of 2 branches (OM1 and OM2) for large (severe) infarcts. Progression of heart failure was evaluated by assessing scar size, the left ventricular ejection fraction, hematology, cardiac serum biochemical biomarkers, ST elevation, and clinical observation. All parameters were assessed at baseline and at 3 wk and 3 mo after infarction, except that clinical observation of the animals was conducted daily. The different parameters differed in their usefulness: some verified appropriate creation of the model, whereas others enabled assessment of the progression of heart disease. We hypothesize that myocardial scar size, as a function of induced ischemia, coupled with left ventricular ejection fraction are predictive indicators of postinfarction cardiac dysfunction.


Assuntos
Insuficiência Cardíaca/patologia , Infarto do Miocárdio/patologia , Animais , Cicatriz/patologia , Coração/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Ovinos
6.
Biochim Biophys Acta Mol Basis Dis ; 1863(12): 3277-3285, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28962896

RESUMO

OBJECTIVE: The transcription factor Krüppel-like factor 14 (KLF14) has been associated with type 2 diabetes and high-density lipoprotein-cholesterol (HDL-C) through genome-wide association studies. The mechanistic underpinnings of KLF14's control of metabolic processes remain largely unknown. We studied the physiological roles of KLF14 in a knockout (KO) mouse model. METHODS: Male whole body Klf14 KO mice were fed a chow or high fat diet (HFD) and diet induced phenotypes were analyzed. Additionally, tissue-specific expression of Klf14 was determined using RT-PCR, RNA sequencing, immunoblotting and whole mount lacZ staining. Finally, the consequences of KLF14 loss-of-function were studied using RNA sequencing in tissues with relatively high Klf14 expression levels. RESULTS: KLF14 loss-of-function did not affect HFD-induced weight gain or insulin resistance. Fasting plasma concentrations of glucose, insulin, cholesterol, HDL-C and ApoA-I were also comparable between Klf14+/+ and Klf14-/- mice on chow and HFD. We found that in mice expression of Klf14 was the highest in the anterior pituitary (adenohypophysis), lower but detectable in white adipose tissue and undetectable in liver. Loss of KLF14 function impacted on the pituitary transcriptome with extracellular matrix organization as the primary affected pathway and a predicted link to glucocorticoid receptor signaling. CONCLUSIONS: Whole body loss of KLF14 function in male mice does not result in metabolic abnormalities as assessed under chow and HFD conditions. Mostly likely there is redundancy for the role of KLF14 in the mouse and a diverging function in humans.


Assuntos
Fatores de Transcrição Kruppel-Like/deficiência , Síndrome Metabólica/metabolismo , Animais , Apolipoproteína A-I/metabolismo , Colesterol/metabolismo , HDL-Colesterol/metabolismo , Dieta Hiperlipídica , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Glucose/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Síndrome Metabólica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glucocorticoides/metabolismo , Análise de Sequência de RNA
7.
J Am Assoc Lab Anim Sci ; 52(5): 571-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24041213

RESUMO

Despite the increasing use of rabbits as companion animals and models for biomedical research, rabbits have not been extensively studied to identify an efficacious postsurgical analgesic that does not cause systemic complications. The synergy of NSAID and systemic opioids is well-documented, and their combined use reduces the amount of either drug required for adequate analgesia. We measured fecal corticosterone metabolites (FCM) in rabbits after a minimally invasive vascular cut-down procedure. Rabbits received buprenorphine (0.03 mg/kg SC every 12 h for 3 d), meloxicam (0.2 mg/kg SC every 24 h for 3 d), buprenorphine-meloxicam (0.01 mg/kg-0.1 mg/kg SC every 24 h for 3 d), or a single dose of 0.5% bupivacaine (0.5 mL) infused locally at the incision site. By day 3 after surgery, buprenorphine, meloxicam, and bupivacaine groups showed elevated FCM levels, which continued to rise until day 7 and then gradually returned to baseline by day 28. In the buprenorphine-meloxicam group, FCM was relatively unchanged until day 3, when treatment was discontinued, and then began to rise. Rabbits in the buprenorphine-meloxicam group gained more weight over the 28-d study than did those in the other 3 treatment groups. This study shows that in rabbits low-dose buprenorphine administered with meloxicam effectively mitigates the FCM response that develops after surgery without the adverse effects associated with higher doses.


Assuntos
Analgesia/veterinária , Buprenorfina/administração & dosagem , Glucocorticoides/metabolismo , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/veterinária , Tiazinas/administração & dosagem , Tiazóis/administração & dosagem , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anestésicos Locais/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Peso Corporal/efeitos dos fármacos , Bupivacaína/administração & dosagem , Buprenorfina/efeitos adversos , Corticosterona/metabolismo , Quimioterapia Combinada , Fezes , Masculino , Meloxicam , Procedimentos Cirúrgicos Minimamente Invasivos/veterinária , Dor Pós-Operatória/metabolismo , Coelhos , Tiazinas/efeitos adversos , Tiazóis/efeitos adversos
8.
J Virol ; 87(11): 6507-11, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23536663

RESUMO

We report that swine influenza virus-like substitutions T200A and E227A in the hemagglutinin (HA) of the 2009 pandemic influenza virus alter its pathogenesis and transmission. Viral replication is increased in mammalian cells. Infected mice show increased disease as measured by weight loss and lethality. Transmission in ferrets is decreased in the presence of both substitutions, suggesting that amino acids 200T and 227E are adaptive changes in the HA of swine origin influenza viruses associated with increased transmission and decreased pathogenesis.


Assuntos
Substituição de Aminoácidos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/mortalidade , Influenza Humana/transmissão , Animais , Regulação para Baixo , Feminino , Furões , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1/química , Vírus da Influenza A Subtipo H1N1/metabolismo , Influenza Humana/epidemiologia , Influenza Humana/virologia , Camundongos , Camundongos Endogâmicos DBA , Pandemias , Regulação para Cima , Virulência
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