RESUMO
A 12-year-old, 3 kg spayed female mixed-breed dog was evaluated to assess a 1-year history of intermittent right forelimb lameness that did not have adequate response to nonsteroidal anti-inflammatory drugs. The radiographic study performed under sedation showed multifocal radiolucent areas affecting both the right humerus and scapula with focal soft tissue swelling; a CT scan confirmed the existence of an aggressive and invasive soft tissue mass affecting the scapulohumeral joint. Fine needle aspiration results suggested a low-grade synovial sarcoma and therefore a scapulectomy was performed. The biopsy showed spindle to stellated cells immersed in a basophilic and mucinous (myxoid) matrix with mild to moderate anisocytosis, moderate anisokaryosis, some binucleated cells and sporadic multinucleated cells. These findings are consistent with low-grade synovial myxosarcoma, a not well described synovial neoplasm that can mimic other commonly seen joint tumors or even septic arthritis on radiographs. The purpose of this case report is to describe the first reported synovial myxosarcoma affecting the scapulohumeral joint of a small dog.
Assuntos
Doenças do Cão , Mixossarcoma , Animais , Cães , Feminino , Doenças do Cão/patologia , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/diagnóstico , Doenças do Cão/cirurgia , Mixossarcoma/veterinária , Mixossarcoma/patologia , Mixossarcoma/diagnóstico , Mixossarcoma/cirurgia , Sarcoma Sinovial/veterinária , Sarcoma Sinovial/patologia , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/diagnóstico por imagem , Escápula/patologia , Escápula/diagnóstico por imagem , Coxeadura Animal/etiologiaRESUMO
A 30-year-old Standardbred gelding was referred for chronic pleural effusion. Thoracic ultrasound revealed marked bilateral pleural effusion and a large heterogeneous mass within the cranial mediastinum, which extended from the right 5th to the 11th intercostal space. Subsequently, on thoracic radiographs, the cranial mediastinal mass was confirmed, and a nodular interstitial pattern was identified in the lungs. Because of progressive clinical deterioration of the patient, the owners elected humane euthanasia and necropsy was performed. The mediastinal mass was consistent with an ectopic thyroid carcinoma, and the pulmonary nodules represented equine multinodular pulmonary fibrosis (EMPF). This case report describes a type of mediastinal tumor not previously described in horses. Moreover, it shows the need of including EMPF as a possible differential diagnosis for a nodular interstitial pulmonary pattern in conjunction with a mediastinal or other masses.
Assuntos
Infecções por Herpesviridae/veterinária , Doenças dos Cavalos , Fibrose Pulmonar/veterinária , Neoplasias da Glândula Tireoide/veterinária , Animais , Cavalos , Masculino , MediastinoAssuntos
Carcinogênese/metabolismo , Senescência Celular/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Neoplasias/fisiopatologia , Transdução de Sinais/fisiologia , Animais , Proliferação de Células/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Camundongos , Camundongos Knockout , Proteína Supressora de Tumor p53/metabolismoRESUMO
Endothelin-1 (ET-1) has been implicated in the development of pulmonary fibrosis, based on its capacity in vitro to promote extracellular matrix (ECM) production and contraction, and on studies showing elevated expression of ET-1 and its receptors in patients with pulmonary fibrosis. However, the in vivo fibrogenic effect of ET-1 is not well characterized. We used the adenoviral-mediated gene transfer of ET-1 to overexpress ET-1 transiently in murine lungs by intratracheal administration. An increased expression of ET-1 for 3 to 10 days after injection resulted in a moderate but reversible fibrotic response, peaking on Day 14 after infection and characterized by the deposition of ECM components, myofibroblast formation, and a significant inflammatory infiltrate, mainly in the peribronchiolar/perivascular region. Adenoviral-mediated ET-1 overexpression activated focal adhesion kinase (FAK) both in vitro, using primary murine lung fibroblasts, and in vivo, intratracheally administered in the lungs of mice. The inhibition of FAK with the compound PF-562,271 prevented ET-1-mediated collagen deposition and myofibroblast formation, thereby preventing the development of lung fibrosis. In conclusion, we demonstrate that the overexpression of ET-1 directly in the lungs of mice can initiate a fibrogenic response characterized by increased ECM deposition and myofibroblast formation, and that this effect of ET-1 can be prevented by inhibition of FAK. Our data suggest that the ET-1/FAK axis may contribute importantly to the pathogenesis of fibrotic disorders, and highlight FAK as a potential therapeutic target in these devastating diseases.
Assuntos
Adenoviridae/genética , Endotelina-1/biossíntese , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Fibrose Pulmonar/enzimologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular , Células Cultivadas , Endotelina-1/genética , Ativação Enzimática , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Vetores Genéticos , Humanos , Indóis/farmacologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/patologia , Miofibroblastos/fisiologia , Fosforilação , Processamento de Proteína Pós-Traducional , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Escleroderma Sistêmico/enzimologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Sulfonamidas/farmacologia , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
AIMS: The epidermal growth factor-like protein Delta-like 1 (DLK1) regulates multiple differentiation processes. It resembles NOTCH ligands structurally and is considered a non-canonical ligand. Given the crucial role of the NOTCH pathway in angiogenesis, we hypothesized that DLK1 could regulate angiogenesis by interfering with NOTCH. We therefore investigated the expression and function of DLK1 in the vascular endothelium and its role in the regulation of angiogenesis. METHODS AND RESULTS: We report DLK1 expression in the endothelium of different species, including human, cow, pig, and mouse. Angiogenesis was studied by using in vitro and in vivo models of angiotube formation in endothelial cells, retinal phenotypes in Dlk1-null mice, and vessel development in zebrafish. DLK1 overexpression strongly inhibited angiotube formation, whereas lung endothelial cells from Dlk1-null mice were highly angiogenic. In vivo studies demonstrated DLK1-mediated inhibition of neovessel formation and revealed an altered pattern of angiogenesis in the retinas of Dlk1-null mice. The expression of human DLK1 in zebrafish embryos severely altered the formation of intersegmental vessels, while knockdown of the orthologous gene was associated with ectopic and increased tumour-induced angiogenesis. NOTCH-dependent signalling as determined by gene expression reporters was inhibited by the presence of DLK1 in vascular endothelial cells. In contrast, Dlk1-null mice showed increased levels of NOTCH downstream targets, such as Snail and Slug. CONCLUSION: Our results unveil a novel inhibitory role for DLK1 in the regulation of angiogenesis, mediated by antagonism of the NOTCH pathway, and establish the basis for investigating its action in pathological settings.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Neovascularização Fisiológica , Animais , Proteínas de Ligação ao Cálcio , Bovinos , Células Cultivadas , Células Endoteliais/metabolismo , Camundongos , Neovascularização Patológica/etiologia , Receptores Notch/antagonistas & inibidores , Neovascularização Retiniana/etiologia , Transdução de Sinais , Cicatrização , Peixe-ZebraRESUMO
OBJECTIVE: To characterize the pathways induced by transforming growth factor beta1 (TGFbeta1) that lead to the expression of endothelin 1 (ET-1) in human dermal fibroblasts, and to study the effects of TGFbeta1 and ET-1 on the acquisition of a profibrotic phenotype and assess the contribution of the TGFbeta1/ET-1 axis to skin wound healing and fibrosis in vivo. METHODS: The mechanism of induction of ET-1 expression by TGFbeta1 and its effect on the expression of alpha-smooth muscle actin and type I collagen were studied in human dermal fibroblasts, in experiments involving the TGFbeta receptor inhibitor GW788388 and the ET receptor antagonist bosentan, by real-time reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay, immunofluorescence, Western blotting, and promoter/reporter transient transfection analyses. Experiments assessing dermal wound healing in mice were performed with adenovirus-driven overexpression of active TGFbeta1 and ET-1, with or without treatment with bosentan. The contributions of TGFbeta1 and ET-1 to the fibrotic response were also assessed in a mouse model of bleomycin-induced skin fibrosis, by histologic, immunohistochemical, RT-PCR, and protein analyses. RESULTS: TGFbeta1 induced ET-1 expression in human dermal fibroblasts through Smad- and activator protein 1/JNK-dependent signaling. The ability of TGFbeta1 to induce the expression of profibrotic genes was dependent on ET-1. Adenovirus-mediated overexpression of TGFbeta1 and ET-1 in mouse skin was associated with accelerated wound closure, increased fibrogenesis, and excessive scarring. Treatment with bosentan prevented the effects of TGFbeta1. In the bleomycin-induced fibrosis model, treatment with GW788388 and bosentan prevented the fibrotic response. CONCLUSION: Our results strongly support the notion that the TGFbeta1/ET-1 axis has a role in wound repair and skin fibrosis. ET-1 receptor antagonists, such as bosentan, may represent a useful therapeutic tool in the treatment of excessive scarring and fibrosis-related diseases.
Assuntos
Endotelina-1/fisiologia , Pele/patologia , Fator de Crescimento Transformador beta1/fisiologia , Cicatrização/fisiologia , Actinas/análise , Animais , Benzamidas/farmacologia , Bleomicina , Western Blotting , Bosentana , Células Cultivadas , Colágeno Tipo I/análise , Ensaio de Imunoadsorção Enzimática , Feminino , Fibroblastos/fisiologia , Fibrose/fisiopatologia , Camundongos , Camundongos Endogâmicos C3H , Pirazóis/farmacologia , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/efeitos dos fármacos , Sulfonamidas/farmacologia , TransfecçãoRESUMO
OBJECTIVE: To determine, in a sheep model, the effect of a short-term progestative treatment on growth dynamics and functionality of induced corpora lutea. DESIGN: Observational, model study. SETTING: Public university. PATIENT(S): Sixty adult female sheep. INTERVENTION(S): Synchronization and induction of ovulation with progestogens and prostaglandin analogues; ovarian ultrasonography, blood sampling, and ovariectomy. MAIN OUTCOME MEASURE(S): Determination of pituitary function and morphologic characteristics, expression of luteinizing hormone (LH) receptors, and progesterone secretion of corpora lutea. RESULT(S): The use of progestative pretreatments for assisted conception affect the growth patterns, the expression of LH receptors, and the progesterone secretion of induced corpora lutea. CONCLUSION(S): The current study indicates, in a sheep model, the existence of deleterious effects from progestogens on functionality of induced corpora lutea.