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Universidade Federal Do Ceará Faculdade De Medicina Departamento De Fisiologia E Farmacologia Programa De Pós-Graduação Em Farmacologia

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Universidade Federal Do Ceará Faculdade De Medicina Departamento De Fisiologia E Farmacologia Programa De Pós-Graduação Em Farmacologia UNIVERSIDADE FEDERAL DO CEARÁ FACULDADE DE MEDICINA DEPARTAMENTO DE FISIOLOGIA E FARMACOLOGIA PROGRAMA DE PÓS-GRADUAÇÃO EM FARMACOLOGIA RICARDO DE OLIVEIRA LIMA PAPEL DA ADENOSINA E DA VIA PI3K/AKT/mTOR NO EFEITO PROTETOR DO PRÉ-CONDICIONAMENTO ISQUÊMICO REMOTO NA FORMAÇÃO DE LESÃO POR PRESSÃO EXPERIMENTAL FORTALEZA 2019 RICARDO DE OLIVEIRA LIMA PAPEL DA ADENOSINA E DA VIA PI3K/AKT/mTOR NO EFEITO PROTETOR DO PRÉ-CONDICIONAMENTO ISQUÊMICO REMOTO NA FORMAÇÃO DE LESÃO POR PRESSÃO EXPERIMENTAL Tese apresentada ao programa de Pós- graduação em Farmacologia da Universidade Federal do Ceará, como requisito parcial para obter o título de Doutor em Farmacologia. Área de concentração: Ciências Biológicas II. Orientadora: Profa. Dra. Mariana Lima Vale. FORTALEZA 2019 Dados Internacionais de Catalogação naPublicação Universidade Federal do Ceará Biblioteca Universitária Gerada automaticamente pelo módulo Catalog, mediante os dados fornecidos pelo autor L71p Lima, Ricardo de Oliveira. Papel da adenosina e da via PI3K/AKT/mTOR no efeito protetor do pré- condicionamento isquêmico remoto na formação de lesão por pressão experimental / Ricardo de Oliveira Lima. – 2019. 171 f. : il. color. Tese (doutorado) – Universidade Federal do Ceará, Faculdade de Medicina, Programa de Pós-Graduação em Farmacologia, Fortaleza, 2019. Orientação: Prof. Dr. Mariana Lima Vale. 1. Pré-condicionamento isquêmico remoto. 2. Lesão por Pressão. 3. Adenosina. I. Título. CDD 615.1 RICARDO DE OLIVEIRA LIMA PAPEL DA ADENOSINA E DA VIA PI3K/AKT/mTOR NO EFEITO PROTETOR DO PRÉ-CONDICIONAMENTO ISQUÊMICO REMOTO NA FORMAÇÃO DE LESÃO POR PRESSÃO EXPERIMENTAL Tese apresentada ao programa de Pós- graduação em Farmacologia da Universidade Federal do Ceará, como requisito parcial para obter o título de Doutor em Farmacologia. Área de concentração: Ciências Biológicas II Aprovado em: 25/01/2019. BANCA EXAMINADORA _____________________________________ Profa. Dra. Mariana Lima Vale (Orientadora) Universidade Federal do Ceará (UFC) __________________________________________ Prof. Dr. Thiago Antônio Moretti de Andrade UNIARARAS - Fundação Hermínio Ometto (FHO) __________________________________________ Prof. Dr. Felipe Domingos de Sousa. Instituto Federal de Educação, Ciência e Tecnologia do Ceará (IFCE) __________________________________________ Profa. Dra. Edna Maria Camelo Chaves Universidade Estadual do Ceará (UECE) __________________________________________ Profa. Dra. Ingrid Samantha Tavares de Figueiredo Centro Universitário Estácio do Ceará A Deus, meu Amado, por quem provém tudo que existe. Aos meus pais, Francisco Ferreira Lima e Francisca de Oliveira Lima, que exemplos espontâneos e verdadeiros de caráter e altruísmos, formaram a maior parte do que sou hoje. A meus irmãos Carlos Gilson e Sheila Stephanie, e a meu amigo Felipe Almeida pessoas que pude contar e que me apoiaram em todos os momentos. As minhas sobrinhas Maria Beatriz e Maria Laís, bálsamos e oásis na aridez do caminho da vida. Dedico! AGRADECIMENTOS À Professora Dra. Mariana Lima Vale que mais que orientadora foi uma amiga ou uma mãe, sempre tratando a todos com paciência, respeito, carinho e bom humor. Agradeço além da orientação, o exemplo de professora e ser humano que me passou durante esta longa caminhada. As estomaterapeuta e professoras Eurideia Castro, Miyoko Sakuraba, Beatriz Yamada e Gizele Azevedo pelos ensinamentos clínicos essenciais para minha vida profissional e acadêmica, conhecimentos estes que influenciaram nas tomadas de decisões ao decorrer deste estudo. Ao Diego Bernardes estudante de iniciação científica, que compartilhou o trabalho árduo dessa tese, não só auxiliando como IC, mas me incentivando a cada etapa desse trabalho através de seu bom humor e palavras de conforto. A Patrícia Sâmara, Elthon Ferreira e Débora Cavalcante pela ajuda nos momentos difíceis. A professora Deysi Wong, ao professor Roberto César pelo apoio e ajuda nos testes de qPCR e E, bem como incentivando e ajudando nos momentos difíceis. Aos meus amigos Paulo Giordane, Marcílio Sousa, Silvana Feitosa, Zelma Costa, Michel Platinir, Dayse Salazar, Thayna Barboza pelo companheirismo, amizade e apoio emocional. Aos meus chefes Angela Cristina Bonfim e Júnior Santos, e demais colegas de trabalho pelo apoio, compreensão e ajuda nos momentos difíceis da pós- graduação. Ao Wesley Ribeiro veterinário do biotério do NPDM pela ajuda, apoio e compreensão durante os experimentos. A Laura e todo os funcionários do Departamento de Fisiologia e Farmacologia. Ao departamento de fisiologia e farmacologia da UFC, bem como a própria Universidade Federal do Ceará. À Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) pelo apoio financeiro oferecido. “In principio erat Verbum, et Verbum erat apud Deum, et Deus erat Verbum. Hoc erat in principio apud Deum. Omnia per ipsum facta sunt: et sine ipso factum est nihil, quod factum est. In ipso vita erat, et vita erat lux hominum: et lux in tenebris lucet, et tenebræ eam non comprehenderunt.” (São João 1:1-5) RESUMOA lesão por pressão (LP) é um tipo de lesão de isquemia e reperfusão (I/R) que atinge considerável número de pessoas no mundo inteiro, e o grande desafio atual é um método preventivo eficaz e de baixo custo para este problema. O pré- condicionamento isquêmico remoto (PCIR) vem se destacando cada vez mais como um método simples e barato de prevenção de lesões de I/R. Diante disso, torna-se importante avaliar o efeito do PCIR sobre a LP. O presente estudo tem como objetivo avaliar o efeito protetor do PCIR na formação da LP experimental e investigar a participação da adenosina, seus receptores e a via PI3K/AKT/mTOR nesse processo. Para isso utilizou-se camundongos Swiss machos, utilizando modelo experimental de LP não invasivo. O trabalho se desenvolveu em 2 etapas: na primeira verificou-se o melhor protocolo de proteção por PCIR através da área da lesão, escala EWAT (Experimental Wound Assessment Tool), escores histopatológicos para lesão por pressão e teste MDA (malondialdeido). Os parâmetros avaliados mostraram que o protocolo de 4 dias foi o mais eficaz em prevenir a LP, sendo o escolhido para dar seguimento para a 2ª etapa, na qual avaliou-se o possível mecanismo de ação envolvido na proteção. Para investigar a participação da adenosina foram administrados os antagonistas de receptores A1, A2A, A2B e o inibidor da adenenosina deaminase (ADA) antes do PCIR em animais submetidos a LP. Foi observado que a adenosina é importante no efeito do PCIR e que provavelmente os receptores A2A e A1 estão envolvidos. Adicionalmente, foi investigado a participação da via PI3K/AKT/mTOR através de qPCR e imunofluorescência para esses marcadores. O PCIR realizado em animais com LP aumentou a expressão de genica de PI3K e marcação de fosfo-mTOR, mostrando que a via está ativada e que o antagonista do receptor A2A inibe essa ativação. Os marcadores como p38MAPK e VEGF também tiveram sua expressão inibidas pelo efeito do PCIR. O efeito sobre o estresse nitrosativo foi visto pela marcação de nitrotirosina, no qual o antagonista de A2A também reverteu o efeito do PCIR. Diante disso, a adenosina está envolvida no mecanismo protetor do PCIR, possivelmente através dos receptores A1 e A2A, sendo A2A mais participativo nesse mecanismo, e que a via PI3/Akt/mTOR possivelmente esteja envolvida no efeito protetor do PCIR mediante ativação pela adenosina. Palavras-chave: Pré-condicionamento isquêmico remoto. Lesão por Pressão. Adenosina. ABSTRACT THE ROLE OF ADENOSINE AND THE PI3K / AKT / mTOR PATHWAY IN THE PROTECTIVE EFFECT OF REMOTE ISCHEMIC PRECONDITIONING IN THE FORMATION OF EXPERIMENTAL PRESSURE INJURY Pressure injury (PI) is a type of ischemia and reperfusion injury (I/R) that affects a considerable number of people worldwide, and the current major challenge is an effective and low-cost preventive method for this problem. Remote ischemic preconditioning (RIPC) has been increasingly highlighted as a simple and inexpensive method of preventing I/R injuries. Therefore, it is important to assess the effect of the PCIR on PI. The aim of the present study is to evaluate the protective effect of RIPC on the formation of experimental PI and to understand the role of adenosine, its receptors and PI3K/AKT/mTOR pathway in this process. Male Swiss mice were submitted to noninvasive experimental PI model. The work was developed in two stages, the first tested the best protection protocol by RIPC, and the second evaluated the possible mechanism of action involved in protection. In the first stage, the best RIPC protocol was evaluated through the lesion area, EWAT (Experimental Wound Assessment Tool) scale, histopathological scores for pressure lesion and MDA test (malondialdehyde). The parameters evaluated showed that the 4-day protocol was the most effective in preventing PI, being chosen to follow up for the second stage. To investigate the involvement of adenosine, the A1, A2A, A2B receptor antagonists and the adenenosine deaminase (ADA) inhibitor were administered prior to RIPC in animals submitted to PI. The lesion area, EWAT scale and histopathological scores were evaluated. The results show that adenosine is important in the effect of PCIR and that A2A and A1 receptors are probably involved. Furthermore, the participation of the PI3K / AKT / mTOR pathway through qPCR and immunofluorescence for these markers was investigated. RIPC performed on animals with PI increases the expression of PI3K gene and phospho-mTOR labeling, showing that the pathway is activated and that the A2A receptor antagonist
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