RESUMEN
A major constraint in the study of Plasmodium falciparum malaria, including vaccine development, lies on the parasite's strict human host specificity and therefore the shortage of animal experimental models able to harbor human plasmodia. The best experimental models are neo-tropical primates of the genus Saimiri and Aotus, but they require splenectomy to reduce innate defenses for achieving high and consistent parasitemias, an important limitation. Clodronate-liposomes (CL) have been successfully used to deplete monocytes/macrophages in several experimental models. We investigated whether a reduction in the numbers of phagocytic cells by CL would improve the development of P. falciparum parasitemia in non-splenectomized Saimiri sciureus monkeys. Depletion of S. sciureus splenocytes after in vitro incubation with CL was quantified using anti-CD14 antibodies and flow cytometry. Non-infected and P. falciparum-infected S. sciureus were injected intravenously twice a week with either CL at either 0.5 or 1 mL (5 mg/mL) or phosphate buffered saline (PBS). Animals were monitored during infection and treated with mefloquine. After treatment and euthanasia, spleen and liver were collected for histological analysis. In vitro CL depleted S. sciureus splenic monocyte/macrophage population in a dose- and time-dependent manner. In vivo, half of P. falciparum-infected S. sciureus treated with CL 0.5 mL, and two-thirds of those treated with CL 1 mL developed high parasitemias requiring mefloquine treatment, whereas all control animals were able to self-control parasitemia without the need for antimalarial treatment. CL-treated infected S. sciureus showed a marked decrease in the degree of splenomegaly despite higher parasitemias, compared to PBS-treated animals. Histological evidence of partial monocyte/macrophage depletion, decreased hemozoin phagocytosis and decreased iron recycling was observed in both the spleen and liver of CL-treated infected S. sciureus. CL is capable of promoting higher parasitemia in P. falciparum-infected S. sciureus, associated with evidence of partial macrophage depletion in the spleen and liver. Macrophage depletion by CL is therefore a practical and viable alternative to surgical splenectomy in this experimental model.
Asunto(s)
Ácido Clodrónico/farmacología , Macrófagos/efectos de los fármacos , Malaria Falciparum/parasitología , Monocitos/efectos de los fármacos , Parasitemia/inducido químicamente , Plasmodium falciparum/crecimiento & desarrollo , Animales , Ácido Clodrónico/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Haplorrinos , Humanos , Liposomas , Hígado/citología , Masculino , Fagocitosis/efectos de los fármacos , Saimiri , Bazo/citología , Factores de TiempoRESUMEN
OBJECTIVES: To compare histologically and imaginologically the bone structure of rats' mandibles treated with bisphosphonates (BPs) and rats that did not receive BPs. METHODS: Thirty-four rat specimens (Rattus novergicus, Wistar strain) were divided into three groups: (i) 12 rats treated with zoledronic acid; (ii) 12 rats treated with clodronate; and (iii) the control group, containing 10 rats that received saline solution. All individuals were exposed to cone beam computed tomography (CBCT). The images were processed and analyzed to obtain the Hounsfield scores, using the software OsiriX 7.0. Sixty-eight histological slides were obtained from the specimens and stained with hematoxylin and eosin (HE). Using the software Adobe Photoshop CS6, the histological areas containing non-vital bone were identified and quantified. RESULTS: Non-vital bone presented positive association with the zoledronic acid and clodronate groups. Statistically, no significant difference in bone density was observed among the groups. CONCLUSIONS: Based on the results, the BP therapy alone was sufficient to induce osteonecrosis. In addition, the CBCT was not a sensible method for detection of the early signs of bone modification in individuals under BP therapy.
Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Ácido Clodrónico/farmacología , Difosfonatos/farmacología , Imidazoles/farmacología , Mandíbula/efectos de los fármacos , Animales , Tomografía Computarizada de Haz Cónico , Femenino , Mandíbula/diagnóstico por imagen , Mandíbula/patología , Microscopía , Ratas , Ratas Wistar , Ácido ZoledrónicoRESUMEN
Despite intense investigation, the mechanisms of the different forms of trigeminal neuropathic pain remain substantially unidentified. The transient receptor potential ankyrin 1 channel (encoded by TRPA1) has been reported to contribute to allodynia or hyperalgesia in some neuropathic pain models, including those produced by sciatic nerve constriction. However, the role of TRPA1 and the processes that cause trigeminal pain-like behaviours from nerve insult are poorly understood. The role of TRPA1, monocytes and macrophages, and oxidative stress in pain-like behaviour evoked by the constriction of the infraorbital nerve in mice were explored. C57BL/6 and wild-type (Trpa1(+/+)) mice that underwent constriction of the infraorbital nerve exhibited prolonged (20 days) non-evoked nociceptive behaviour and mechanical, cold and chemical hypersensitivity in comparison to sham-operated mice (P < 0.05-P < 0.001). Both genetic deletion of Trpa1 (Trpa1(-/-)) and pharmacological blockade (HC-030031 and A-967079) abrogated pain-like behaviours (both P < 0.001), which were abated by the antioxidant, α-lipoic acid, and the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin (both P < 0.001). Nociception and hypersensitivity evoked by constriction of the infraorbital nerve was associated with intra- and perineural monocytic and macrophagic invasion and increased levels of oxidative stress by-products (hydrogen peroxide and 4-hydroxynonenal). Attenuation of monocyte/macrophage increase by systemic treatment with an antibody against the monocyte chemoattractant chemokine (C-C motif) ligand 2 (CCL2) or the macrophage-depleting agent, clodronate (both P < 0.05), was associated with reduced hydrogen peroxide and 4-hydroxynonenal perineural levels and pain-like behaviours (all P < 0.01), which were abated by perineural administration of HC-030031, α-lipoic acid or the anti-CCL2 antibody (all P < 0.001). The present findings propose that, in the constriction of the infraorbital nerve model of trigeminal neuropathic pain, pain-like behaviours are entirely mediated by the TRPA1 channel, targeted by increased oxidative stress by-products released from monocytes and macrophages clumping at the site of nerve injury.
Asunto(s)
Hiperalgesia/fisiopatología , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Neuralgia/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Canales de Potencial de Receptor Transitorio/fisiología , Acetanilidas/antagonistas & inhibidores , Acetanilidas/farmacología , Acetofenonas/farmacología , Animales , Quimiocina CCL2/antagonistas & inhibidores , Ácido Clodrónico/farmacología , Hiperalgesia/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Noqueados , Monocitos/metabolismo , Neuralgia/metabolismo , Oximas/antagonistas & inhibidores , Oximas/farmacología , Purinas/antagonistas & inhibidores , Purinas/farmacología , Canal Catiónico TRPA1 , Ácido Tióctico/farmacología , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/genéticaRESUMEN
INTRODUCTION: Orthodontic anchorage is one of the most challenging aspects of Orthodontics. Preventing undesired movement of teeth could result in safer and less complicated orthodontic treatment. Recently, several reviews have been published about the effects of different molecules on bone physiology and the clinical side effects in Orthodontics. However, the effects of local application of these substances on the rate of orthodontic tooth movement have not been assessed. OBJECTIVES: The aim of this research was to analyze the scientific evidence published in the literature about the effects of different molecules on orthodontic anchorage. METHODS: The literature was systematically reviewed using PubMed/Medline, Scopus and Cochrane databases from 2000 up to July 31st, 2014. Articles were independently selected by two different researchers based on previously established inclusion and exclusion criteria, with a concordance Kappa index of 0.86. The methodological quality of the reviewed papers was performed. RESULTS: Search strategy identified 270 articles. Twenty-five of them were selected after application of inclusion/exclusion criteria, and only 11 qualified for final analysis. Molecules involved in orthodontic anchorage were divided into three main groups: osteoprotegerin (OPG), bisphosphonates (BPs) and other molecules (OMs). CONCLUSIONS: Different drugs are able to alter the bone remodeling cycle, influencing osteoclast function and, therefore, tooth movement. Thus, they could be used in order to provide maximal anchorage while preventing undesired movements. OPG was found the most effective molecule in blocking the action of osteoclasts, thereby reducing undesired movements.
Asunto(s)
Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Difosfonatos/farmacología , Difosfonatos/uso terapéutico , Métodos de Anclaje en Ortodoncia/métodos , Osteoprotegerina/farmacología , Osteoprotegerina/uso terapéutico , Movilidad Dentaria/tratamiento farmacológico , Movilidad Dentaria/prevención & control , Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Animales , Remodelación Ósea/efectos de los fármacos , Celecoxib/farmacología , Celecoxib/uso terapéutico , Ácido Clodrónico/farmacología , Ácido Clodrónico/uso terapéutico , Diclofenaco/farmacología , Diclofenaco/uso terapéutico , Humanos , Imidazoles/farmacología , Imidazoles/uso terapéutico , Interferón gamma/farmacología , Interferón gamma/uso terapéutico , Isoxazoles/farmacología , Isoxazoles/uso terapéutico , Lactonas/farmacología , Lactonas/uso terapéutico , Ratones , Osteoclastos/efectos de los fármacos , Pamidronato , Ratas , Resveratrol , Estilbenos/farmacología , Estilbenos/uso terapéutico , Sulfonas/farmacología , Sulfonas/uso terapéutico , Técnicas de Movimiento Dental , Ácido ZoledrónicoRESUMEN
Introduction: Orthodontic anchorage is one of the most challenging aspects of Orthodontics. Preventing undesired movement of teeth could result in safer and less complicated orthodontic treatment. Recently, several reviews have been published about the effects of different molecules on bone physiology and the clinical side effects in Orthodontics. However, the effects of local application of these substances on the rate of orthodontic tooth movement have not been assessed.Objectives: The aim of this research was to analyze the scientific evidence published in the literature about the effects of different molecules on orthodontic anchorage.Methods: The literature was systematically reviewed using PubMed/Medline, Scopus and Cochrane databases from 2000 up to July 31st, 2014. Articles were independently selected by two different researchers based on previously established inclusion and exclusion criteria, with a concordance Kappa index of 0.86. The methodological quality of the reviewed papers was performed.Results: Search strategy identified 270 articles. Twenty-five of them were selected after application of inclusion/exclusion criteria, and only 11 qualified for final analysis. Molecules involved in orthodontic anchorage were divided into three main groups: osteoprotegerin (OPG), bisphosphonates (BPs) and other molecules (OMs).Conclusions: Different drugs are able to alter the bone remodeling cycle, influencing osteoclast function and, therefore, tooth movement. Thus, they could be used in order to provide maximal anchorage while preventing undesired movements. OPG was found the most effective molecule in blocking the action of osteoclasts, thereby reducing undesired movements.
Introdução: a ancoragem ortodôntica é um dos aspectos mais desafiadores da Ortodontia. A prevenção de movimentos dentários indesejados poderia resultar em um tratamento ortodôntico mais seguro e menos complexo. Recentemente, foram publicadas várias revisões de literatura sobre os efeitos de diferentes substâncias na fisiologia do tecido ósseo e os efeitos colaterais clínicos na Ortodontia. Porém, os efeitos da aplicação local dessas substâncias no grau de movimentação dentária ortodôntica não foram avaliados.Objetivos: o objetivo da presente pesquisa foi analisar a evidência científica publicada na literatura sobre os efeitos de diferentes substâncias na ancoragem ortodôntica.Métodos: a literatura foi sistematicamente revisada utilizando-se as bases de dados PubMed/Medline, Scopus e Cochrane, de 2000 a 31 de julho de 2014. Os artigos foram selecionados, de maneira independente, por dois pesquisadores diferentes, tendo como base critérios de inclusão e exclusão previamente estabelecidos, com um índice Kappa de concordância de 0,86. A qualidade metodológica dos artigos revisados foi analisada.Resultados: a estratégia de pesquisa identificou 270 artigos; 25 artigos foram selecionados após a aplicação dos critérios de inclusão e exclusão, mas apenas 11 foram qualificados para a análise final. As substâncias envolvidas na ancoragem ortodôntica foram divididas em três grupos principais: osteoprotegerina (OPG), bisfosfonatos (BFs) e outras substâncias (OSs).Conclusões: diferentes substâncias são capazes de alterar o ciclo de remodelação óssea, influenciando na função dos osteoclastos e, portanto, na movimentação dentária. Sendo assim, essas substâncias podem ser utilizadas para promover o máximo de ancoragem e prevenir movimentos indesejados. A OPG foi a substância mais eficaz no bloqueio da ação dos osteoclastos, reduzindo os movimentos indesejados.
Asunto(s)
Humanos , Animales , Ratas , Difosfonatos/uso terapéutico , Difosfonatos/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Acetilcisteína/uso terapéutico , Acetilcisteína/farmacología , Diclofenaco/uso terapéutico , Diclofenaco/farmacología , Remodelación Ósea/efectos de los fármacos , Ácido Clodrónico/uso terapéutico , Ácido Clodrónico/farmacología , Métodos de Anclaje en Ortodoncia/métodos , Celecoxib/uso terapéutico , Celecoxib/farmacología , Resveratrol , Ácido Zoledrónico , Pamidronato , Imidazoles/farmacologíaRESUMEN
Irritant contact dermatitis (ICD) is an inflammatory reaction caused by chemical toxicity on the skin. The P2X7 receptor (P2X7R) is a key mediator of cytokine release, which recruits immune cells to sites of inflammation. We investigated the role of P2X7R in croton oil (CrO)-induced ICD using in vitro and in vivo approaches. ICD was induced in vivo by CrO application on the mouse ear and in vitro by incubation of murine macrophages and dendritic cells (DCs) with CrO and ATP. Infiltrating cells were identified by flow cytometry, histology and myeloperoxidase (MPO) determination. Effects of the ATP scavenger apyrase were assessed to investigate further the role of P2X7R in ICD. Animals were also treated with N-1330, a caspase-1 inhibitor, or with clodronate, which induces macrophage apoptosis. CrO application induced severe inflammatory Gr1(+) cell infiltration and increased MPO levels in the mouse ear. Selective P2X7R antagonism with A438079 or genetic P2X7R deletion reduced the neutrophil infiltration. Clodronate administration significantly reduced Gr1(+) cell infiltration and local IL-1ß levels. In vitro experiments confirmed that A438079 or apyrase treatment prevented the increase in IL-1ß that was evoked by macrophage and DC incubation with CrO and ATP. These data support a key role for P2X7 in ICD-mediated inflammation via modulation of inflammatory cells. It is tempting to suggest that P2X7R inhibition might be an alternative ICD treatment.
Asunto(s)
Movimiento Celular/fisiología , Dermatitis por Contacto/patología , Dermatitis por Contacto/fisiopatología , Neutrófilos/patología , Receptores Purinérgicos P2X7/fisiología , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Ácido Clodrónico/farmacología , Aceite de Crotón/efectos adversos , Dermatitis por Contacto/metabolismo , Modelos Animales de Enfermedad , Técnicas In Vitro , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridinas/farmacología , Receptores Purinérgicos P2X7/deficiencia , Receptores Purinérgicos P2X7/genética , Tetrazoles/farmacologíaRESUMEN
BACKGROUND: The aim of this study was to compare clodronate and zoledronic acid regarding their influence on the repair of surgical wounds in maxillae (soft tissue wound and tooth extraction) and their relation to osteonecrosis. MATERIAL AND METHODS: Thirty-four Wistar rats were allocated into three groups according to the treatment received: (i) 12 animals treated with zoledronic acid, (ii) 12 animals treated with clodronate and (iii) 10 animals that were given saline solution. All animals were subjected to tooth extractions and surgically induced soft tissue injury. Histological analysis of the wound sites was performed by means of hematoxylin-eosin (H&E) staining and immunohistochemical staining for receptor activator of nuclear factor-kB ligand (RANKL), osteoprotegerin (OPG), von Willebrand factor, and caspase-3. RESULTS: The zoledronic acid group showed higher incidence of non-vital bone than did the clodronate group at the tooth extraction site. At the soft tissue wound site, there were no significant differences in non-vital bone between the test groups. RANKL, OPG, von Willebrand factor, and caspase-3 did not show significant differences between the groups for both sites of surgical procedures. CONCLUSION: Both of the bisphosphonates zoledronic acid and clodronate are capable of inducing maxillary osteonecrosis. Immunohistochemical analysis suggests that the involvement of soft tissues as the initiator of osteonecrosis development is less probable than has been pointed out.
Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Ácido Clodrónico/farmacología , Difosfonatos/farmacología , Imidazoles/farmacología , Maxilar/cirugía , Animales , Carga Bacteriana , Caspasa 3/análisis , Tejido Conectivo/efectos de los fármacos , Tejido Conectivo/patología , Epitelio/efectos de los fármacos , Epitelio/patología , Femenino , Maxilar/efectos de los fármacos , Maxilar/microbiología , Maxilar/patología , Enfermedades Maxilares/inducido químicamente , Enfermedades Maxilares/patología , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/lesiones , Osteonecrosis/inducido químicamente , Osteonecrosis/patología , Osteoprotegerina/análisis , Ligando RANK/análisis , Ratas , Ratas Wistar , Extracción Dental , Alveolo Dental/efectos de los fármacos , Alveolo Dental/microbiología , Alveolo Dental/patología , Cicatrización de Heridas/efectos de los fármacos , Ácido Zoledrónico , Factor de von Willebrand/análisisRESUMEN
BACKGROUND: Cyclosporine A (CsA)-induced chronic nephrotoxicity is characterized by renal dysfunction and interstitial fibrosis. Early and progressive renal macrophage influx, correlating with latter interstitial fibrotic areas, has been associated with CsA treatment. This study investigated the role of macrophages, the nitric oxide (NO) pathway, and the oxidative stress on chronic CsA nephrotoxicity. METHODS: The macrophages were depleted by clodronate liposomes. Animals were distributed into four groups: vehicle (olive oil for 21 days), CsA 7.5 mg/kg per day (21 days), CsA plus clodronate (5 mg/mL intraperitoneally on days -4, 1, 4, 11, and 18 of CsA treatment), or vehicle plus clodronate. On day 22, glomerular filtration rate, renal blood flow, renal tubulointerstitial fibrosis, CsA blood levels, serum malondialdehyde and renal tissue immunohistochemistry for macrophages, inducible NO synthase, transforming growth factor-beta, nuclear factor-kbeta, alpha-smooth muscle actin, vimentin, and nitrotyrosine were assessed. RESULTS: CsA-induced increase in the macrophage was prevented by clodronate. Macrophage depletion attenuated the reductions in the glomerular filtration rate and renal blood flow, the development of tubulointerstitial fibrosis, malondialdehyde increase and increases in nuclear factor-kbeta, transforming growth factor-beta, vimentin, inducible NO synthase, and nitrotyrosine expression provoked by CsA. Clodronate did not affect alpha-smooth muscle actin expression and CsA blood levels. CONCLUSIONS: Renal macrophage influx plays an important role in CsA-induced chronic nephrotoxicity. The NO pathway and oxidative stress are likely mechanisms involved in the genesis of this form of renal injury.
Asunto(s)
Ácido Clodrónico/farmacología , Ciclosporina/farmacología , Tasa de Filtración Glomerular/fisiología , Inmunosupresores/farmacología , Macrófagos/fisiología , Animales , Anticuerpos/farmacología , Ciclosporina/sangre , Diuresis/efectos de los fármacos , Diuresis/fisiología , Tasa de Filtración Glomerular/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Riñón/efectos de los fármacos , Riñón/fisiología , Pruebas de Función Renal , Macrófagos/efectos de los fármacos , Masculino , FN-kappa B/inmunología , Óxido Nítrico/fisiología , Ratas , Ratas Wistar , Circulación Renal/efectos de los fármacos , Circulación Renal/fisiología , Tirosina/inmunología , Resistencia Vascular/efectos de los fármacos , Vimentina/inmunologíaRESUMEN
Snake venom metalloproteinases (SVMPs) play a prominent role in the local and systemic manifestations of viperid snakebite envenomations. Thus, the possibility of using metalloproteinase inhibitors in the treatment of these envenomations is a promising therapeutic alternative. This study assessed the ability of two metalloproteinase inhibitors, the biphosphonate clodronate and the tetracycline doxycycline, to inhibit proteolytic, hemorrhagic, coagulant and defibrinogenating effects of Bothrops asper venom. Both compounds were able to inhibit these activities, at concentrations in the mM range, when incubated with venom prior to testing. However, when inhibition of hemorrhage was assessed in assays involving independent injection of venom and drug, inhibition was poor, even when these compounds were injected immediately after envenomation. These findings support the concept that the effectiveness of compounds, such as clodronate and doxycycline, whose inhibitory action on SVMPs is based on zinc chelation alone, is limited, and stress the view that more specific molecules are required for an effective inhibition of SVMPs in vivo.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Ácido Clodrónico/farmacología , Venenos de Crotálidos/toxicidad , Doxiciclina/farmacología , Inhibidores Enzimáticos/farmacología , Hemorragia/tratamiento farmacológico , Metaloproteasas/antagonistas & inhibidores , Animales , Bothrops , Venenos de Crotálidos/enzimología , Hemorragia/inducido químicamente , Humanos , Concentración 50 Inhibidora , Ratones , Ratones EndogámicosRESUMEN
This study investigates the role of tumor nitric oxide (NO) and vascular regulation in tumor ulceration following high-dose tumor necrosis factor-alpha (TNF) treatment. Using TNF-responsive (MethA) and nonresponsive (LL2) mouse tumors, tumor NO concentration was measured with an electrochemical sensor and tumor blood flow by Doppler ultrasound. Mice were also pretreated with a selective inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. Tumors harvested from TNF-treated mice were cryosectioned and immunostained for murine macrophages, or/and iNOS. MethA tumor-bearing mice were depleted of macrophages. Pre- and post-TNF tumor NO levels were measured continuously, and mice were followed for gross tumor response. In MethA tumors, TNF caused a 96% response rate, and tumor NO concentration doubled. Tumor blood flow decreased to 3% of baseline by 4 hr and was sustained at 24 hr and 10 days post-TNF. Selective NO inhibition with 1400 W blocked NO rise and decreased response rate to 38%. MethA tumors showed tumor infiltration by macrophages post-TNF and the pattern of macrophage immunostaining overlapped with iNOS immunostaining. Depletion of macrophages inhibited tumor NO increase and response to TNF. LL2 tumors had a 0% response rate to TNF and exhibited no change in NO concentration. Blood flow decreased to 2% of baseline by 4 hr, recovered to 56% by 24 hr and increased to 232% by 10 days. LL2 tumors showed no infiltration by macrophages post-TNF. We conclude that TNF causes tumor infiltrating, macrophage-derived iNOS-mediated tumor NO rise and sustained tumor blood flow shutdown, resulting in tumor ulceration in the responsive tumor.
Asunto(s)
Antineoplásicos/farmacología , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/tratamiento farmacológico , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Ácido Clodrónico/administración & dosificación , Ácido Clodrónico/farmacología , Selectina E/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibrosarcoma/enzimología , Fibrosarcoma/metabolismo , Regulación Enzimológica de la Expresión Génica , Inmunohistoquímica , Liposomas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/metabolismo , Flujo Sanguíneo Regional , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
Megakaryocytopoiesis is the process by which stem cells go through a process of commitment, proliferation and differentiation leading to the production of platelets. In the mouse, this process is accomplished within the bone marrow (BM) and spleen microenvironment and is carried out by regulatory molecules and accessory cells including macrophages, fibroblasts and endothelial-like cells. Previously, we have reported that macrophage depletion following administration of liposomal clodronate (LIP-CLOD) provokes enhancement of both, megakaryocytopoiesis and thrombocytopoiesis. In this report, we investigated the changes in the compartment of megakaryocyte progenitor cells (MK-CFU), their correlation with plasmatic thrombopoietin (TPO) and TPO transcription levels after macrophage depletion. LIP-CLOD-treated mice showed an increase of the MK-CFU in BM and spleen. Concerning TPO plasma levels, kinetic studies revealed a 1.5- and 1.3-fold increase in the TPO concentration at 12 and 24 hr of treatment. We also show evidence of regulation of TPO transcription in the liver and spleen. Although empty liposomes also enhanced TPO gene regulation in these organs, transcriptional TPO up regulation correlated with an increase of protein synthesis only in those animals where macrophages were effectively removed. Taken together, these results suggest that BM and spleen macrophages derived signalling regulates negatively the megakaryocyte compartment.
Asunto(s)
Macrófagos/fisiología , Megacariocitos/fisiología , Transducción de Señal , Trombopoyesis/fisiología , Trombopoyetina/sangre , Animales , Médula Ósea/efectos de los fármacos , Ácido Clodrónico/farmacología , Ensayo de Unidades Formadoras de Colonias , Femenino , Interleucina-11/farmacología , Interleucina-3/farmacología , Masculino , Ratones , Bazo/efectos de los fármacos , Trombopoyetina/genética , Trombopoyetina/farmacología , Transcripción Genética , Regulación hacia ArribaRESUMEN
Os bisfosfonatos são drogas que inibem a reabsorção óssea e são utilizados clinicamente para o controle das hipercalcemias, calcificações ectópicas e osteoporose. Pacientes com insuficiência renal crônica em diálise e transplantados poderiam se beneficiar do uso dessas drogas. Entretanto, por serem drogas de excreção renal, exigem cautela e conhecimento da sua farmacologia. Nos pacientes em diálise, começam a ser empregados para o controle do hiperparatiroidismo, melhorando a hipercalcemia e permitindo o uso de calcitriol. Em transplantados, vêm sendo utilizados para controlar a perda de massa óssea no pós-transplante, causada por persistência do hiperparatiroidismo ou pelo uso das drogas imunossupressoras, principalmente os corticóides.
Asunto(s)
Humanos , Ácido Clodrónico/farmacología , Corticoesteroides , Alendronato , Calcitriol , Diálisis , Hiperparatiroidismo , Insuficiencia Renal Crónica/complicaciones , Trasplante de Riñón , Osteoporosis , Resorción Ósea/tratamiento farmacológicoRESUMEN
Immune thrombocytopenic purpura (ITP) is an autoimmune disease related to the presence of elevated levels of platelet-associated immunoglobulin, or autoantibodies. In recent years the importance of macrophage Fc gamma receptors in the uptake of platelets in ITP has been confirmed. Although in patients with ITP the platelet destruction occurs in liver and spleen, in this present experimental mouse model the liver was the principal organ of sequestration of sensitized platelets. The uptake in the spleen, bone marrow, lung, and kidneys was negligible and not different from that in control animals. In addition, the trapped platelets did not return to circulation, and new cells derived from the platelet-storage pool or new thrombocytogenesis were necessary to restore the platelet count. The depletion of splenic and hepatic murine macrophages by liposome-encapsulated clodronate (lip-clod) was studied as a new strategy for ITP treatment. Lip-clod inhibits, in a dose-dependent manner, the antibody-induced thrombocytopenia. Moreover, lip-clod treatment rapidly restored (24 hours) the platelet count in thrombocytopenic animals to hematologic safe values, and despite additional antiplatelet antiserum treatment, mice were able to maintain this level of platelets at least up to 48 hours. The bleeding times in lip-clod-treated animals was not different from those in controls, demonstrating that the hemostasis was well controlled in these animals. The results presented in this study demonstrate that lip-clod treatment can be effective in the management of experimental ITP. (Blood. 2000;96:2834-2840)