Estudo experimental da inibição do VEGF na regeneração hepática
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Sousa, Eros Luiz de
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Introdução: extensas ressecções e transplantes de partes do fígado são possíveis, graças à sua capacidade regenerativa que é dependente da ativação do fator de crescimento vascular endotelial (VEGF) o qual também regula angiogênese. O bevacizumabe (BV), anticorpo monoclonal inibidor do VEGF é um neoadjuvante amplamente utilizado no tratamento de cânceres restringindo a densidade microvascular, podendo causar efeitos indesejáveis na cicatrização pós-operatória e na regeneração hepática. Objetivo: avaliar a regeneração hepática (RH), pós hepatectomia a 70%, sob ação de uma dose (5mg/kg) de BV num modelo experimental murino, durante 15 dias. Métodos: utilizaram-se 32 ratos Wistar submetidos à hepatectomia parcial (HP), separados em dois grupos conforme o tratamento controle (C) tratados com solução fisiológica e BV tratados com BV, subdivididos conforme o tempo de observação (48 horas e 15 dias) em C48, BV48 e C15, BV15. Os efeitos do BV na RH foram avaliados nas avaliações ponderais, função hepática (albumina, transaminases, bilirrubinas e relação APRI). No fígado remanescente avaliaram-se atividade mitótica, densidade microvascular (angiogênese), proliferação nuclear, histopatologia para investigar fibrose, edema e congestão. Empregaram-se ANOVA e T-Student com p≤0,05 para as análises estatísticas. Resultados: no décimo quinto dia pós-HP e tratamento com BV, não ocorreram diferenças nas avaliações ponderais (p=0,0691), na função hepática e nos índices mitóticos (p=0,1576). Porém, houve diminuição na viabilidade celular (p=0,0000), densidade microvascular (p=0,0162) e piora na ocorrência de alterações histopatológicas como fibrose, edema e congestão hepáticas. Conclusão: a dose única de BV, não causou, ao décimo quinto dia de evolução, alterações ponderais, bioquímicas séricas (albumina, bilirrubinas e transaminases) e dos índices mitóticos. Contudo induziu diminuição da densidade microvascular, viabilidade celular e alterações histopatológicas hepáticas como edema, congestão e fibrose.
Background: extensive liver resections and transplants of liver parts are possible thanks to its regenerative capacity which is dependent on vascular endothelial growth factor (VEGF) activation which also regulates the angiogenesis. Bevacizumab (BV), a monoclonal antibody VEGF inhibitor, is a neoadjuvant treatment of cancers widely used, restricting microvascular density and may cause undesirable effects on postoperative healing and liver regeneration (LR). Objective: to determine the effect of a single dose (5mg/kg) of BV in LR. Methods: 32 rats submitted to partial hepatectomy (PH) were separated into two groups according to saline solution (C) or BV (BV) treatment. According to the observation time (48h and 15 days) they were subdivided in C48 and BV48 and C15 and BV15 sub-groups. In LR, the BV effects were evaluated by weight variation and liver function (albumin, transaminase, bilirubin and APRI ratio) and in remaining liver were evaluated, mitotic activity, microvascular density (angiogenesis), nuclear proliferation, histopathology for fibrosis, edema and congestion. For statistical analysis, the ANOVA and T-Student test was used (of statistical significance when p≤0.05). Results: on the fifteenth day after PH and BV treatment, there were no differences in weight evaluations (p=0.0691), liver function and mitotic indexes (p=0.1576). However, there was a decrease in cell viability (p=0.0000), microvascular density (p = 0.0162) and worsening in the occurrence of histopathological changes such as liver fibrosis, edema and congestion. Conclusion: a single BV dose, on the fifteenth day of evolution has no significant effect in weight evolution, serum biochemical evaluations (albumin, bilirubin and transaminases) and mitotic index. However, it induced microvascular density decreased, cell viability and liver histopathological changes such as fibrosis, edema and congestion.
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Background: extensive liver resections and transplants of liver parts are possible thanks to its regenerative capacity which is dependent on vascular endothelial growth factor (VEGF) activation which also regulates the angiogenesis. Bevacizumab (BV), a monoclonal antibody VEGF inhibitor, is a neoadjuvant treatment of cancers widely used, restricting microvascular density and may cause undesirable effects on postoperative healing and liver regeneration (LR). Objective: to determine the effect of a single dose (5mg/kg) of BV in LR. Methods: 32 rats submitted to partial hepatectomy (PH) were separated into two groups according to saline solution (C) or BV (BV) treatment. According to the observation time (48h and 15 days) they were subdivided in C48 and BV48 and C15 and BV15 sub-groups. In LR, the BV effects were evaluated by weight variation and liver function (albumin, transaminase, bilirubin and APRI ratio) and in remaining liver were evaluated, mitotic activity, microvascular density (angiogenesis), nuclear proliferation, histopathology for fibrosis, edema and congestion. For statistical analysis, the ANOVA and T-Student test was used (of statistical significance when p≤0.05). Results: on the fifteenth day after PH and BV treatment, there were no differences in weight evaluations (p=0.0691), liver function and mitotic indexes (p=0.1576). However, there was a decrease in cell viability (p=0.0000), microvascular density (p = 0.0162) and worsening in the occurrence of histopathological changes such as liver fibrosis, edema and congestion. Conclusion: a single BV dose, on the fifteenth day of evolution has no significant effect in weight evolution, serum biochemical evaluations (albumin, bilirubin and transaminases) and mitotic index. However, it induced microvascular density decreased, cell viability and liver histopathological changes such as fibrosis, edema and congestion.
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Palavras-chave
regeneração hepática , inibidores da ingiogênese , bevacizumab , VEGF , ratos wistar , CNPQ::CIENCIAS DA SAUDE