RESUMO
Purpose/Aim: Substance P-NK-1R signaling has been implicated in fibrotic tendinopathies and myositis. Blocking this signaling with a neurokinin 1 receptor antagonist (NK1RA) has been proposed as a therapeutic target for their treatment.Materials and Methods: Using a rodent model of overuse injury, we pharmacologically blocked Substance P using a specific NK1RA with the hopes of reducing forelimb tendon, muscle and dermal fibrogenic changes and associated pain-related behaviors. Young adult rats learned to pull at high force levels across a 5-week period, before performing a high repetition high force (HRHF) task for 3 weeks (2 h/day, 3 days/week). HRHF rats were untreated or treated in task weeks 2 and 3 with the NK1RA, i.p. Control rats received vehicle or NK1RA treatments.Results: Grip strength declined in untreated HRHF rats, and mechanical sensitivity and temperature aversion increased compared to controls; these changes were improved by NK1RA treatment (L-732,138). NK1RA treatment also reduced HRHF-induced thickening in flexor digitorum epitendons, and HRHF-induced increases of TGFbeta1, CCN2/CTGF, and collagen type 1 in flexor digitorum muscles. In the forepaw upper dermis, task-induced increases in collagen deposition were reduced by NK1RA treatment.Conclusions: Our findings indicate that Substance P plays a role in the development of fibrogenic responses and subsequent discomfort in forelimb tissues involved in performing a high demand repetitive forceful task.
Assuntos
Transtornos Traumáticos Cumulativos/patologia , Derme/patologia , Músculo Esquelético/patologia , Transdução de Sinais , Substância P/metabolismo , Tendões/patologia , Animais , Restrição Calórica , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose , Proteínas Musculares/metabolismo , Fosforilação , Ratos Sprague-Dawley , Receptores da Neurocinina-1/metabolismo , Análise e Desempenho de Tarefas , Tendinopatia/patologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Autoreactive CD4+ T cells can transfer experimental allergic neuritis (EAN) to naive recipients. In order to further analyze the role of these T cells and their corresponding cytokines in EAN, we studied the expression of mRNA for IFN-gamma, IL-4, and IL-10 in the cauda equina of rats with EAN using a quantitative competitive reverse transcriptase PCR method. Nerves were studied on days 0 (pre-immunization), 10 (disease onset), 13 (clinical progression), 16 (disease peak), as well as 20, 24, and 34 post immunization (recovery). IFN-gamma messages increased at disease onset and peaked at day 13 p.i. IL-10 message remained at a very low level at disease onset and surged at day 16. Both messages were low in recovery stage. IL-4 message was undetectable at any time point. These data suggest a pro-inflammatory role of IFN-gamma and anti-inflammatory role of IL-10 in EAN lesions. It is also possible that a clonal switch from Th1 to Th2 occurs in EAN lesions during the disease course.
Assuntos
Cauda Equina/imunologia , Citocinas/genética , Neurite Autoimune Experimental/imunologia , Actinas/genética , Animais , Feminino , Expressão Gênica/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos LewRESUMO
Two hundred fifteen patients infected with human immunodeficiency virus (HIV) participated in a prospective longitudinal study of HIV-related heart disease. Evaluation included signal-averaged electrocardiography and echocardiography. Fifteen patients underwent endomyocardial biopsy, 5 had cardiovascular symptoms and 10 did not. Cardiac myocytes or dendritic cells were prepared by individual cell microdissection to sort them from other cell types such as interstitial cells or circulating blood elements. HIV proviral sequences were amplified in samples of 15 to 20 cells of each type by multiplex, nested, polymerase chain reaction and hybridized to 32P-labeled probes specific for regions within the gag and pol genes of HIV-1. The results showed the presence of HIV sequences in myocytes of 2 of 5 patients with cardiac symptoms and in 6 of 10 without. Thus, symptomatic HIV cardiomyopathy did not appear to be a direct consequence of the virus on myocardial cells. In dendritic cells, HIV sequences were detected in 5 of 5 patients with cardiac symptoms and in 8 of 10 with apparently normal ventricular function. Furthermore, dendritic cells were somewhat more numerous in the myocardium of symptomatic than asymptomatic patients. Our studies are the first to directly detect the HIV genome in purified cardiac myocytes from patients with and without cardiac dysfunction. Our findings do not support a direct role of the virus in myocardial dysfunction. However, the results do suggest that the interstitial dendritic cells may be involved in some manner in the development of cardiac dysfunction observed in HIV-infected patients.
Assuntos
Células Dendríticas/microbiologia , Infecções por HIV/microbiologia , Infecções por HIV/fisiopatologia , HIV-1/isolamento & purificação , Ventrículos do Coração/microbiologia , Miocárdio/citologia , Reação em Cadeia da Polimerase/métodos , Adulto , Sequência de Bases , Biópsia , Southern Blotting , Cardiopatias/microbiologia , Ventrículos do Coração/fisiopatologia , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Dados de Sequência Molecular , Estudos ProspectivosRESUMO
From 1993 to 1995, approximately 10% of the clinically healthy northern elephant seals (Mirounga angustirostris) at The Marine Mammal Center in California exhibited a large unexplained increase in their white blood cell (WBC) count. In these animals, WBC counts ranged from 28,780 to 125,000/mm3, with a mean of 50,087/mm3. Significant correlations between the leukocytosis and weight gain and day of admittance were identified, but no correlation existed between leukocytosis and general state of health, sex, length of stay, or diet. Bone marrow contamination of blood samples, erroneous automated leukocyte counts, and leukogram changes consistent with subclinical inflammation were the major factors contributing to the elevated WBC counts in these apparently clinically healthy animals.
Assuntos
Leucócitos/citologia , Focas Verdadeiras/sangue , Animais , Feminino , Contagem de Leucócitos/veterinária , Masculino , Valores de ReferênciaRESUMO
Experimental allergic encephalomyelitis (EAE) can be downregulated by intravenous (iv) administration of myelin basic protein (MBP). In this report we show that downregulation of EAE by two 500-microgram doses of MBP administered iv before immunization was associated with reduced encephalitogenicity of both spleen and lymph node cells (day 12 postimmunization) in adoptive transfer studies. However, efficient downregulation of EAE by two 500-microgram iv doses of MBP on days 10 and 11 after active immunization (at the time of disease onset) was associated with no significant change in the encephalitogenicity of lymph node cells, but a complete abrogation of the ability of spleen cells (both at day 12 postimmunization) to transfer EAE compared to controls. Furthermore, coculture of spleen cells from rats tolerized by iv MBP on days 10 and 11 after active immunization with MBP with MBP-reactive T cells resulted in a decreased ability of the spleen T cells to transfer EAE compared to effector cells in monoculture. In contrast, coculture of MBP-reactive T cells with spleen cells from rats tolerized by iv MBP on days 14 and 7 before active immunization resulted in increased disease in recipient rats. These results suggest that reversal of clinical EAE by iv injection of MBP at the time of disease onset is due at least in part to a T cell control mechanism located in the spleen and suggest the presence of splenocyte regulatory cells that can suppress the ability of encephalitogenic T cells to induce EAE.