Assuntos
Procedimentos Cirúrgicos Cardíacos , Prestação Integrada de Cuidados de Saúde/organização & administração , Países em Desenvolvimento , Acessibilidade aos Serviços de Saúde/organização & administração , Cooperação Internacional , Cardiopatia Reumática/cirurgia , África/epidemiologia , Procedimentos Cirúrgicos Cardíacos/economia , Comportamento Cooperativo , Prestação Integrada de Cuidados de Saúde/economia , Países em Desenvolvimento/economia , Custos de Cuidados de Saúde , Acessibilidade aos Serviços de Saúde/economia , Humanos , Cardiopatia Reumática/diagnóstico , Cardiopatia Reumática/economia , Cardiopatia Reumática/mortalidade , Fatores de TempoRESUMO
Magnetic nanoparticles (MNPs) have gained much attention due to their unique properties such as biocompatibility and biodegradability as well as magnetic and heat-medicated characteristics. Due to these inherent properties, MNPs have been widely used in various biomedical applications including targeted drug delivery and hyperthermia-based therapy. Hyperthermia is a promising approach for the thermal activation therapy of several diseases, including pulmonary diseases. Additionally, due to their large loading capacity and controlled release ability, several MNP-based drug delivery systems have been emerged for treatment of cystic fibrosis and lung cancer. This review provides an overview on the unique properties of MNPs and magnetic-mediated hyperthermia with emphasis on the recent biomedical applications of MNPs in treatment of both lung cancer and cystic fibrosis.
Assuntos
Fibrose Cística/terapia , Sistemas de Liberação de Medicamentos/métodos , Hipertermia Induzida/métodos , Neoplasias Pulmonares/terapia , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Animais , Fibrose Cística/patologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/uso terapêutico , Técnicas de Transferência de Genes , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologiaRESUMO
Valve interstitial cells populate aortic valve cusps and have been implicated in aortic valve calcification. Here we investigate a common in vitro model for aortic valve calcification by characterizing nodule formation in porcine aortic valve interstitial cells (PAVICs) cultured in osteogenic (OST) medium supplemented with transforming growth factor beta 1 (TGF-ß1). Using a combination of materials science and biological techniques, we investigate the relevance of PAVICs nodules in modeling the mineralised material produced in calcified aortic valve disease. PAVICs were grown in OST medium supplemented with TGF-ß1 (OST+TGF-ß1) or basal (CTL) medium for up to 21 days. Murine calvarial osteoblasts (MOBs) were grown in OST medium for 28 days as a known mineralizing model for comparison. PAVICs grown in OST+TGF-ß1 produced nodular structures staining positive for calcium content; however, micro-Raman spectroscopy allowed live, noninvasive imaging that showed an absence of mineralized material, which was readily identified in nodules formed by MOBs and has been identified in human valves. Gene expression analysis, immunostaining, and transmission electron microscopy imaging revealed that PAVICs grown in OST+TGF-ß1 medium produced abundant extracellular matrix via the upregulation of the gene for Type I Collagen. PAVICs, nevertheless, did not appear to further transdifferentiate to osteoblasts. Our results demonstrate that 'calcified' nodules formed from PAVICs grown in OST+TGF-ß1 medium do not mineralize after 21 days in culture, but rather they express a myofibroblast-like phenotype and produce a collagen-rich extracellular matrix. This study clarifies further the role of PAVICs as a model of calcification of the human aortic valve.
Assuntos
Valva Aórtica/citologia , Calcinose/metabolismo , Doenças das Valvas Cardíacas/metabolismo , Actinas/metabolismo , Animais , Valva Aórtica/metabolismo , Células Cultivadas , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Análise Espectral Raman , Suínos , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
The use of left ventricular assist devices to induce substantial myocardial recovery with explantation of the device, bridge to recovery (BTR), is an exciting but currently grossly underused application. Recently acquired knowledge relating to BTR and its mechanisms offers unprecedented opportunities to streamline its use and unravel some of the secrets of heart failure with much wider implications. This article reviews the status, challenges, and future of cardiac recovery.
Assuntos
Insuficiência Cardíaca/terapia , Coração Auxiliar/tendências , Apoptose/fisiologia , Terapia Combinada , Proteínas do Citoesqueleto/metabolismo , Remoção de Dispositivo , Técnicas Eletrofisiológicas Cardíacas , Matriz Extracelular/fisiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/reabilitação , Humanos , Imunidade Inata/fisiologia , Proteínas de Membrana/metabolismo , Contração Miocárdica , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Seleção de Pacientes , Cuidados Pós-Operatórios/métodos , Desenho de Prótese , Implantação de Prótese/métodos , Receptores Adrenérgicos beta/fisiologia , Recuperação de Função Fisiológica/fisiologia , Fatores de TempoRESUMO
Adult progenitor cell transplantation has been proposed for the treatment of heart failure, but the mechanisms effecting functional improvements remain unknown. The aim of this study was to test the hypothesis that, in failing hearts treated with cell transplantation, the mechanical properties and excitation-contraction coupling of recipient cardiomyocytes are altered. Adult rats underwent coronary artery ligation, leading to myocardial infarction and chronic heart failure. After 3 wk, they received intramyocardial injections of either 10(7) green fluorescence protein (GFP)-positive bone marrow mononuclear cells or 5 x 10(6) GFP-positive skeletal myoblasts. Four weeks after injection, both cell types increased ejection fraction and reduced cardiomyocyte size. The contractility of isolated GFP-negative cardiomyocytes was monitored by sarcomere shortening assessment, Ca(2+) handling by indo-1 and fluo-4 fluorescence, and electrophysiology by patch-clamping techniques. Injection of either bone marrow cells or skeletal myoblasts normalized the impaired contractile performance and the prolonged time to peak of the Ca(2+) transient observed in failing cardiomyocytes. The smaller and slower L-type Ca(2+) current observed in heart failure normalized after skeletal myoblast, but not bone marrow cell, transplantation. Measurement of Ca(2+) sparks suggested a normalization of sarcoplasmic reticulum Ca(2+) leak after skeletal myoblast transplantation. The increased Ca(2+) wave frequency observed in failing myocytes was reduced by either bone marrow cells or skeletal myoblasts. In conclusion, the morphology, contractile performance, and excitation-contraction coupling of individual recipient cardiomyocytes are altered in failing hearts treated with adult progenitor cell transplantation.
Assuntos
Transplante de Medula Óssea , Cálcio/metabolismo , Mioblastos Esqueléticos/transplante , Contração Miocárdica/fisiologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Transplante de Células-Tronco , Animais , Comunicação Celular/fisiologia , Tamanho Celular , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Cultivadas , Modelos Animais de Doenças , Técnicas Eletrofisiológicas Cardíacas , Masculino , Infarto do Miocárdio/terapia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Volume Sistólico/fisiologiaRESUMO
BACKGROUND: Antibody therapy to inhibit either P-selectin or intercellular adhesion molecule-1 (ICAM-1) has been reported to provide myocardial protection against leukocyte-mediated reperfusion injury. Because these molecules play different roles in the leukocyte-endothelial interaction, co-inhibition of both may achieve further enhanced cardioprotection. In addition, the therapeutic efficacy of such antibody therapy may be affected by the delivery route used. Retrograde intracoronary infusion will offer an effective, direct access to the postcapillary venules, where the target event (leukocyte-endothelial interaction) takes place. We investigated the feasibility and efficiency of the combined antibody therapy targeting both P-selection and ICAM-1 via the retrograde intracoronary route to attenuate myocardial ischemia-reperfusion injury. METHODS AND RESULTS: Lewis rats underwent 30-minute left coronary artery occlusion. Just before reperfusion, anti-P-selectin monoclonal antibody (150 microg/kg), anti-ICAM-1 monoclonal antibody (200 microg/kg), both antibodies together, or control antibody were retrogradely infused into the left cardiac vein. At 24 hours after reperfusion, administration of either anti-P-selectin or anti-ICAM-1 antibody significantly (P<0.05) improved left ventricular ejection fraction and attenuated infarct size (40.6+/-3.2% and 34.8+/-3.5%, respectively) compared with the control (56.8+/-3.4%). This was associated with reduced leukocyte accumulation and improved regional blood flow in the ischemic area. Noticeably, co-administration of both antibodies achieved a much greater reduction in infarct size (19.1+/-3.6%), associated with greater attenuation in leukocyte infiltration, compared with administration of either single antibody. CONCLUSIONS: Combined antibody therapy inhibiting both P-selectin and ICAM-1 via the retrograde intracoronary route could be a promising new strategy for myocardial protection against ischemia-reperfusion injury.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Quimiotaxia de Leucócito/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/imunologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Selectina-P/imunologia , Doença Aguda , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Circulação Coronária , Vasos Coronários , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Estudos de Viabilidade , Ventrículos do Coração/diagnóstico por imagem , Injeções Intravenosas/métodos , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Miocardite/etiologia , Miocardite/patologia , Miocardite/prevenção & controle , Tamanho do Órgão , Ratos , Ratos Endogâmicos Lew , Volume Sistólico , UltrassonografiaRESUMO
BACKGROUND: Calcific aortic valve disease is a common condition and is associated with inflammatory changes and expression of osteoblast-like cell phenotypes, but the cellular mechanisms are unclear. Recent studies identified extracellular ATP and P2Y receptor cascade as important regulators of bone remodeling, whereas its breakdown product, adenosine, is known to have anti-inflammatory properties. We hypothesize that extracellular ATP and adenosine have important roles in regulating osteoblast differentiation in human valve interstitial cells, and that this can be a potential target for therapy. Method and Results- Primary cultures of human valve interstitial cells (ICs) treated for 21 days with osteogenic media, ATP, and ATP-gamma-S (a stable agonist of the P2Y receptor) revealed a significant increase in alkaline phosphatase (ALP) (an osteoblast marker) activity and expression as measured using spectrophotometric assay and immunocytochemistry staining. Valve ICs treated with adenosine alone did not cause an increase in ALP activity; however, adenosine treatment decreased the ALP activity and expression induced by osteogenic media after 21 days of incubation. In addition, atorvastatin inhibited the activity of ALP induced by ATP in human valve ICs, and enzyme studies revealed that atorvastatin upregulated the breakdown of extracellular ATP into adenosine in human valve ICs after 24-hour treatment. CONCLUSIONS: These findings identify a novel role for extracellular nucleotides in inducing osteoblast differentiation in human valve ICs in vitro and provide a potential therapeutic target for preventing the disease progression.
Assuntos
Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/fisiologia , Adenosina/farmacologia , Estenose da Valva Aórtica/metabolismo , Valva Aórtica/patologia , Calcinose/metabolismo , Ácidos Heptanoicos/farmacologia , Osteoblastos/efeitos dos fármacos , Pirróis/farmacologia , Receptores Purinérgicos P2/fisiologia , 5'-Nucleotidase/análise , Adenosina Trifosfatases/análise , Trifosfato de Adenosina/farmacologia , Idoso , Fosfatase Alcalina/análise , Valva Aórtica/citologia , Estenose da Valva Aórtica/tratamento farmacológico , Estenose da Valva Aórtica/patologia , Apirase/análise , Atorvastatina , Biomarcadores , Calcinose/tratamento farmacológico , Calcinose/patologia , Diferenciação Celular , Células Cultivadas/citologia , Células Cultivadas/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ácidos Heptanoicos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Osteoblastos/citologia , Osteoblastos/enzimologia , Osteoblastos/fisiologia , Pirróis/uso terapêutico , Receptores Purinérgicos P2/efeitos dos fármacos , Sistemas do Segundo Mensageiro/efeitos dos fármacosRESUMO
BACKGROUND: There are a number of strategies to restore/preserve endothelial function. We have compared the effects of Cerivastatin (CS) to those of L-arginine (L-ARG) supplementation on the endothelial function of human arterial grafts. METHODS: During coronary artery bypass grafting, specimens of radial artery (RA) and left internal thoracic artery (LITA) were obtained. Specimens were divided into vascular rings, which were incubated with either 10(-6) mol/L CS, 10(-3) mol/L L-ARG, or vehicle (control) for 2 or 24 hours. Endothelial function was examined with acethylcholine (10(-9) to 10(-5) mol/L) following contraction by 3 x 10(-8) mol/L endothelin-1. RESULTS: Although no significant differences were observed in the RA at 2 hours, after 24 hours incubation, endothelium-dependent vasodilatation was significantly higher in CS group (68.4 +/- 5.0%; n = 6) compared to L-ARG group (49.9 +/- 5.4%; n = 7, p < 0.05) and control group (33.8 +/- 2.9%; n = 13, p < 0.0001). In addition, there was a significant increase in L-ARG group compared to control (p < 0.01). After 2 hours incubation of the LITA, CS failed to enhance endothelium-dependent vasodilatation compared to control (44.1 +/- 4.9%; n = 9, vs. 40.0 +/- 5.2%; n = 16, respectively, NS), while L-ARG increased it (64.7 +/- 4.9%; n = 7, p < 0.05 vs. CS and p < 0.01 vs. control). However, this increase disappeared at 24 hours although there was a higher trend of endothelium-dependent vasodilatation in CS group (30.3 +/- 3.7%; n = 8 in L-ARG, 56.5 +/- 8.8%; n = 9 in CS and 41.0 +/- 5.5%; n = 18 in control). CONCLUSIONS: CS preserved endothelium-dependent vasodilatation of RA greater than L-ARG. These findings suggest that the use of statins may be an effective therapeutic strategy to preserve endothelial function in the RA grafts, and could have important implications in the clinical practice.
Assuntos
Arginina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Artéria Torácica Interna/efeitos dos fármacos , Piridinas/farmacologia , Artéria Radial/efeitos dos fármacos , Acetilcolina/farmacologia , Ponte de Artéria Coronária , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Técnicas In Vitro , Fatores de Tempo , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Sensory nerves regulate central and local reflexes such as airway plasma leakage, and cough and their function may be enhanced during inflammation. Evidence suggests that dopamine receptor agonists may inhibit sensory nerve-mediated responses. In this study dopamine inhibited vagal sensory nerve induced microvascular leakage in the rat. In order to characterize the receptor involved rat vagus preparations were utilized. Quinagolide (D(2/3) agonist), ropinirole (D(2/3/4) agonist), SKF 38393 (D(1/5) agonist), AR-C68397AA (Viozan) (dual D(2)/B(2) agonist) and dopamine inhibited hypertonic saline induced depolarization by approximately 50%. Data suggests that AR-C68397AA and quinagolide also inhibited depolarization of the human vagus. The quinagolide response was blocked by sulpiride (D(2/3) antagonist) but not SCH 23390 (D(1/5) antagonist); ropinirole was partially blocked by sulpiride, totally blocked by spiperone (at a concentration that blocks all dopamine receptors) but not by SCH 23390. The response to SKF 38393 was not blocked by sulpiride but was by SCH 23390. The inhibition evoked by AR-C68397AA was only partially blocked by SCH 23390 but not by sulpiride or spiperone whereas dopamine was blocked by spiperone. The effect of dopamine was not stimulus-specific as it inhibited capsaicin-induced depolarization of the rat vagus in a spiperone sensitive manner. In conclusion, dopamine receptor ligands inhibit depolarization of the rat and human vagus. These data suggest that dopamine receptor agonists may be of therapeutic benefit in the treatment of symptoms such as cough and mucus secretion which are evident in respiratory diseases such as asthma and chronic obstructive pulmonary disease.