dc.contributorElsas, Maria Ignez Capella Gaspar
dc.contributorElsas, Pedro Paulo
dc.contributorMartins, Patricia Machado Rodrigues e Silva
dc.contributorAlves Filho, José Carlos Farias
dc.contributorDiaz, Bruno Lourenço
dc.contributorMorrot, Alexandre
dc.contributorMonteiro, Carmen Penido
dc.creatorPinto, Tulio Queto de Souza
dc.date2013-03-22T14:03:31Z
dc.date2013-03-22T14:03:31Z
dc.date2011
dc.date.accessioned2023-09-27T00:15:22Z
dc.date.available2023-09-27T00:15:22Z
dc.identifierPINTO, Tulio Queto de Souza. Mecanismos celulares e sistêmicos de regulação da eosinopoiese: efeitos estimulatórios dos cisteinil-leucotrienos e dos glicocorticóides e efeitos inibitórios da via inos/cd95l e do g-csf. 2011. 157 f. (Doutorado em Biologia Celular e Molecular) – Instituto Oswaldo Cruz, Rio de Janeiro, 2011.
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/6402
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8899012
dc.descriptionA provocação por via respiratória com ovalbumina (OVA) em camundongos sensibilizados promove, na medula óssea (MO), eosinopoiese, resposta exacerbada à Interleucina(IL)-5, e mudanças no padrão de resposta em cultura à eotaxina, à IL- 13 e aos antiinflamatórios não esteroidais (NSAIDs). Em cultura de MO, a Prostaglandina (PG) E2 induz apoptose de eosinófilos, por via dependente de NO sintase indutível (iNOS) e ligante de CD95 (CD95L), enquanto a dexametasona (DEXA) promove eosinopoiese, gerando eosinófilos agregados e morfológicamente imaturos e protege contra da apoptose induzida por PGE2, provavelmente por mecanismos que regulem a expressão ou ativação de integrinas. No presente trabalho avaliamos se: a) in vitro, os efeitos dos NSAIDs, da IL-13 e da eotaxina dependem da produção de cisteinil-leucotrienos (CisLT) e da sinalização via receptor 1 de CisLT (CysLT1R); b) in vitro, a DEXA regula expressão de VLA-4, que promoveria a agregação e imaturidade dos eosinófilos, e se PGE2 contrapõe a ação da DEXA; c) in vivo, G-CSF e dietilcarbamazina (DEC) promoveriam eosinopenia medular e sistemica e se inibiriam a inflamação pulmonar alérgica. Resultados: a) NSAIDs, eotaxina e IL-13 potencializam a eosinopoiese via produção de CisLT e sinalização via CysLT1R. Os NSAIDs ainda protegem os eosinófilos da apoptose induzida por PGE2 exógena. b) A interação farmacológica entre PGE2 e DEXA modificam a ação de ambas, de forma estreitamente relacionada sobre a expressão de VLA-4 e, em condições específicas, esses agentes sinergizam gerando quantidades aumentadas de eosinófilos maduros. c) A DEC, inibidor da síntese de LTs, que na filariose experimental possivelmente atua via iNOS, inibe a eosinopoiese e os efeitos da provocação sobre o pulmão e a MO, através da via iNOS-CD95L. O Fator Estimulante de Colônias de Granulócitos (G-CSF), estimulante da neutropoiese, igualmente inibiu a inflamação pulmonar alérgica através da inibição da eosinopoiese. Este trabalho é parte do projeto intitulado "Eosinofilia na Asma Experimental", licenciado pela Comissão de Ética no Uso de Animais (CEUA) da Fiocruz, sob nos L010/04 e L002/09.
dc.descriptionOur laboratory has previously shown that airway allergen challenge in ovalbumin-sensitized mice rapidly induces an increase in bone-marrow (BM) eosinophil production (eosinopoiesis), along with an increased response to Interleukin(IL)-5 in BM culture, changes in the ex vivo responses to cytokines and immunomodulators, including nonsteroidal anti-inflammatory drugs (NSAIDs) and cysteinyl-leukotrienes (CysLT), and colonization of the lungs by eosinophil progenitors. Early in the course of IL-5-induced eosinophil differentiation in BM culture, Prostaglandin E2 (PGE2) induces apoptosis, through a pathway dependent on the inducible isoform of NO synthase (iNOS) and the ligand for CD95 (CD95L). NSAIDs enhance eosinopoiesis and protect eosinophils in this critical period from exogenous PGE2, through a novel mechanism of action at the celular level. In this study, we show that indomethacin and aspirin act through endogenously synthesized CysLT, by establishing the essential roles of 5-lipoxygenase, LTC4 synthase and CysLT1R receptors, as well as the cytoprotective effect of CysLT against exogenous PGE2. The similarity between the effects of NSAIDs and those of eotaxin and IL-13 prompted us to reevaluate the contribution of endogenous CysLT to the effects of these cytokines. We confirmed that eotaxin and IL-13 act through this mechanism, and expand therefore the list of agents that, through CysLT, enhance eosinopoiesis, protecting immature eosinophils from apoptosis induced through the iNOS-CD95L pathway. Dexamethasone promotes BM eosinopoiesis, generating aggregated, cytologically immature eosinophils, which are nevertheless protected from PGE2- induced apoptosis. We examined therefore the possibility that dexamethasone upregulates integrin expression/activation, thereby maintaining an immature celular phenotype in cultured eosinophils, while PGE2 would have opposite effects on both integrin function and cytological maturation. We show that the proapoptotic effects of PGE2 are profoundly modified by its pharmacological interaction with dexamethasone, paralleling the effects of both drugs on integrins, and leading to a synergic generation of increased numbers of mature eosinophils, in very specific experimental conditions. Diethylcarbamazine (DEC) is an antihelminthic drug that blocks leukotriene synthesis, and possibly acts in experimental filarial infection through iNOS. We have examined, for the first time, the effects of DEC in a model of allergic pulmonary inflammation, showing that DEC is very effective in preventing the impact of airway allergen challenge on BM and lungs, through the in vivo operation of the iNOS-CD95L pathway. Granulocyte Colony-stimulating Factor (G-CSF), which stimulates neutropoiesis, mobilizes CD34+ hemopoietic progenitors from BM, and exerts complex immunoregulatory effects, was shown in our study to have a strong impact in a murine model of allergic pulmonary inflammation. Like DEC, G-CSF suppressed BM eosinopoiesis, although through a different mechanism, since DEC suppressed neutrophilia in the lungs with no effect on BM neutrophilia/neutropoiesis, while G-CSF promoted neutropoiesis and induced blood neutrophilia, even though it suppressed eosinopoiesis. This work was part of the Research Project “Eosinophilia in Experimental Asthma”, licensed by the Committee on the Ethical Use of Laboratory Animals (CEUA) at FIOCRUZ, under numbers L010/04 and L002/09.
dc.formatapplication/pdf
dc.languagepor
dc.publisherInstituto Oswaldo Cruz.
dc.rightsopen access
dc.subjectDietilcarbamazina
dc.subjectIntegrinas
dc.subjectFator Estimulador de Colônias de Granulócitos
dc.subjectDiethylcarbamazine
dc.subjectIntegrins
dc.subjectGranulocyte Colony-Stimulating Factor
dc.subjectDietilcarbamazina
dc.subjectIntegrinas
dc.subjectFator Estimulador de Colônias de Granulócitos
dc.titleMecanismos celulares e sistêmicos de regulação da eosinopoiese: efeitos estimulatórios dos cisteinil-leucotrienos e dos glicocorticóides e efeitos inibitórios da via inos/cd95l e do g-csf
dc.typeThesis


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