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Silvia Passos Andradehttp://lattes.cnpq.br/6317089230891526http://lattes.cnpq.br/1083067444451577Laura Alejandra Ariza Orellano2024-03-13T12:32:39Z2024-03-13T12:32:39Z2015-02-19http://hdl.handle.net/1843/65750Inibidores da xantina oxidase, reguladores da formação de superóxido (O2-), têm sido utilizados para o tratamento de várias formas de isquemia e lesões vasculares, além da sua indicação terapêutica clássica em hiperurecemia e gota. Neste estudo, avaliamos os efeitos do alopurinol na angiogênese inflamatória induzida pelo implante subcutâneo de uma matriz sintética (poliéter-poliuretano) em camundongos (C57/BL6 – 6-7 semanas). Três grupos de animais (n=8 – 15) que receberam por via oral diferentes doses de alopurinol (0,01, 0,1, ou 1,0 mg/kg, respectivamente) começando o tratamento 24 h após implantação, durante a resposta aguda da formação do tecido fibrovascular. Um grupo de animais (n=9) recebeu alopurinol (1,0 mg/kg) na fase crônica do processo (8 dias pós-implante). O alopurinol reduziu de forma dose dependente o conteúdo de hemoglobina, os níveis da citocina VEGF e o número de vasos sanguíneos (parâmetros angiogênicos) nos implantes. Similarmente, houve inibição dos parâmetros inflamatórios (atividade de mieloperoxidase –MPO e n-acetil-β-D glucosaminidase –NAG e os níveis das citocinas, Fator de Necrose Tumoral α – TNF-α e CCL2) após tratamento com o composto. A produção de NO e H2O2 também foi reduzida de forma dose dependente pelo inibidor quando administrado na fase aguda do processo inflamatório, no entanto todos os parâmetros avaliados apresentaram efeito oposto (aumento) quando o alopurinol foi administrado na fase crônica da formação do tecido fibrovascular. Nos parâmetros fibrogênicos, foram observados efeitos antagônicos (Pró e Anti fibrogênico) dependendo da fase do início do tratamento. Em conclusão, os efeitos inibitórios ou estimuladores do alopurinol sobre os componentesangiogênico, inflamatório e fibrogênico do tecido fibrovascular foram dependentes da fase do início do tratamento. Estes achados ampliam o potencial terapêutico do fármaco no controle de doenças fibroproliferativas e no tratamento co-adjuvante na cicatrização de lesões.Xanthine oxidase inhibitors, key regulators of reactive oxygen species, have been used in the treatment of various ischemic conditions and vascular lesions, besides their classical use in hyperurecemia and gout. Here, we have evaluated the effects of allopurinol on inflammatory angiogenesis induced by subcutaneous implantation of polyether-polyurethane matrix in C57/BL6 mice. Groups of animals (n=8 - 15) that received oral administration of allopurinol (0.01, 0.1 or 1.0 mg/kg) were treated 24h after implantation, during the acute formation of the fibrovascular tissue. Another group of animals (n= 9) were treated with allopurinol (1.0 mg/kg) 8 days after implantation for 6 consecutive days (chronic phase). Angiogenesis, was determined by hemoglobin content, VEGF levels and number of vessels intraimplant, inflammation (myeloperoxidase –MPO, n-acetyl-β-D glucosaminidase –NAG, TNF-α and CCL2 levels) were reduced by allopurinol. Similarly, the treatment inhibited nitric oxide and H2O2 production. However, fibrogenesis determined by collagen deposition and levels of TGF-β1 increased in the implants after allopurinol treatment. In marked contrast with the effects of the treatment initiated on the acute phase of the process, allopurinol increased angiogenesis, inflammation, NO, and H2O2 production but reduced collagen and TGF-β1 levels intraimplant when the treatment was started during the chronic inflammatory process. The dual effects of allopurinol described here, extend its range of actions as a potential agent able to modulate the components of the fibrovascular tissue present in both physiological (healing processes) as well as in chronic fibroprolifertive diseases. This modulatory effects depends of thephase at which is treatment is initiated that in turn is dependent on the generation of ROS.porUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em Ciências Biológicas - Fisiologia e FarmacologiaUFMGBrasilICB - INSTITUTO DE CIÊNCIAS BIOLOGICAShttp://creativecommons.org/licenses/by-nc-nd/3.0/pt/info:eu-repo/semantics/openAccessFisiologiaInibidores EnzimáticosIndutores da AngiogêneseInflamaçãoÓxido NítricoAlopurinolXantina OxidaseImplante de Matriz SintéticaAngiogêneseInflamaçãoFibrogêneseÓxido NítricoPeróxido de HidrogênioAvaliação do efeito do inibidor da enzima xantina oxidase (alopurinol) no modelo murino de angiogênese inflamatóriainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALTRABALHO COMPLETO.pdfTRABALHO COMPLETO.pdfapplication/pdf1750940https://repositorio.ufmg.br/bitstream/1843/65750/1/TRABALHO%20COMPLETO.pdf1efa13ad88a17bb37b932a686628d433MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufmg.br/bitstream/1843/65750/2/license_rdfcfd6801dba008cb6adbd9838b81582abMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/65750/3/license.txtcda590c95a0b51b4d15f60c9642ca272MD531843/657502024-03-13 09:32:40.0oai:repositorio.ufmg.br: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ório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2024-03-13T12:32:40Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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