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Inflamação e mecanismos citoprotectores em modelos de lesão pulmonar
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Resumo(s)
Apesar dos avanços científicos sobre a fisiopatologia da Lesão Aguda do Pulmão (LAP) e do Síndroma de Dificuldade Respiratória Aguda (SDRA), as taxas de mortalidade permanecem acima dos 30% e os sobreviventes apresentam um significativo decréscimo na qualidade de vida. O trabalho desenvolvido nesta tese pretende contribuir para o esclarecimento das vias celulares envolvidas no processo inflamatório responsável pela lesão pulmonar, clarificando o papel de vários mediadores inflamatórios no desenvolvimento da lesão pulmonar aguda, utilizando um modelo de queimadura que induz um quadro de inflamação sistémica associado a LAP. Neste contexto, e sabendo a importância do processo oxidativo na LAP/SDRA, avaliámos o efeito do ácido rosmarínico como substância anti-oxidante. Tendo em conta o papel das espécies reactivas de oxigénio na activação do factor de transcrição B (NF-B), e o efeito inibidor da activação deste factor exercido pelo ácido rosmarínico, a actividade citoprotectora exibida por esta substância poderá estar relacionada com um efeito pleiotrópico. A via da cinase do 3- fosfatidilinositol/proteína cinase B (PI3K-Akt) é uma das mais importantes vias celulares na regulação de mecanismos de citoprotecção e sobrevivência celular, sendo o NF-B um dos alvos principais. Com o objectivo de modular esta via, demonstrámos que a administração de eritropoietina reduzia a lesão de órgãos. Um dos alvos a jusante da via PI3K-Akt que poderá mediar os efeitos citoprotectores é a cinase 3da sintase do glicogénio (GSK-3) e na tentativa de elucidar este mecanismo, administrámos TDZD-8, um inibidor desta enzima. Verificámos que a inibição desta enzima apresenta um efeito redutor da lesão de órgãos, podendo explicar, pelo menos parcialmente, o efeito benéfico da insulina e eritropoietina em doentes críticos. A administração de artesunato permitiu avaliar a ligação entre as vias oxidativas, a via do NF-B e a via da PI3K-Akt, utilizando o conceito de “reciclagem” de fármacos antigos para outras indicações. É de realçar que foi possível verificar a existência de uma rede de vias celulares que eram comum a todas as abordagens o que permitiu estudar a interacção entre essas vias, elucidar os mecanismos celulares envolvidos na lesão inflamatória do pulmão conduzindo à identificação de novos mediadores pró-inflamatórios e anti-inflamatórios que poderão ser alvos farmacológicos interessantes na modulação da lesão aguda do pulmão.
Despite the scientific advances on the physiological processes behind Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS), the mortality rates remain over 30% and the survivors experience a significant decrease in their quality of life. The work developed on this thesis intends to contribute to the enlightenment of the cellular pathways involved in the inflammatory process responsible for lung injury, clarifying the role of several inflammatory mediators related to lung injury. With that purpose in mind we used an animal burn model to induce a systemic inflammatory process associated with ALI. In that context, and knowing the importance of the oxidative process in ALI/ARDS we evaluated the effect of rosmarinic acid as an anti-oxidant substance. Given the role of reactive oxygen species in the activation of nuclear factor B (NF-B) and the inhibitory effect of rosmarinic acid of NF-B activation, the cytoprotective effect exhibited by this substance might be related to a pleiotropic effect. The phosphoinositide 3- kinase/protein cinase B (PI3K-Akt) pathway is one of the most important pathways in the regulation of cytoprotective mechanisms and cellular survival, being NF-B one of its most relevant targets. Trying to modulate this pathway we demonstrated that the administration of erythropoietin reduced the multi-organ injury. One of the downstream targets of the PI3K-Akt pathway with the ability to mediate cytoprotective effects is glycogen synthase kinase-3β(GSK-3β), and in the attempt to enlighten this mechanism, we administered TDZD-8, an inhibitor of this enzyme. We demonstrated that inhibition of GSK-3βresults in a reduction of organ injury, which might explain, at least partially, the beneficial effect of insulin and erythropoietin in the critically ill patients. Administration of artesunate allowed the evaluation of the crosstalk between the oxidative, NF-B and PI3K-Akt pathways, using the recycling/repurposing of old drugs for new and innovative indications. It is noteworthy that all pharmacological approaches exhibited crosstalk between a network of cellular pathways, which allowed the study of their interaction and the enlightenment of the mechanisms involved in inflammatory lung injury, allowing for the identification of new anti-inflammatory and pro-inflammatory mediators with the potential of becoming interesting pharmacological targets in the modulation of acute lung injury.
Despite the scientific advances on the physiological processes behind Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS), the mortality rates remain over 30% and the survivors experience a significant decrease in their quality of life. The work developed on this thesis intends to contribute to the enlightenment of the cellular pathways involved in the inflammatory process responsible for lung injury, clarifying the role of several inflammatory mediators related to lung injury. With that purpose in mind we used an animal burn model to induce a systemic inflammatory process associated with ALI. In that context, and knowing the importance of the oxidative process in ALI/ARDS we evaluated the effect of rosmarinic acid as an anti-oxidant substance. Given the role of reactive oxygen species in the activation of nuclear factor B (NF-B) and the inhibitory effect of rosmarinic acid of NF-B activation, the cytoprotective effect exhibited by this substance might be related to a pleiotropic effect. The phosphoinositide 3- kinase/protein cinase B (PI3K-Akt) pathway is one of the most important pathways in the regulation of cytoprotective mechanisms and cellular survival, being NF-B one of its most relevant targets. Trying to modulate this pathway we demonstrated that the administration of erythropoietin reduced the multi-organ injury. One of the downstream targets of the PI3K-Akt pathway with the ability to mediate cytoprotective effects is glycogen synthase kinase-3β(GSK-3β), and in the attempt to enlighten this mechanism, we administered TDZD-8, an inhibitor of this enzyme. We demonstrated that inhibition of GSK-3βresults in a reduction of organ injury, which might explain, at least partially, the beneficial effect of insulin and erythropoietin in the critically ill patients. Administration of artesunate allowed the evaluation of the crosstalk between the oxidative, NF-B and PI3K-Akt pathways, using the recycling/repurposing of old drugs for new and innovative indications. It is noteworthy that all pharmacological approaches exhibited crosstalk between a network of cellular pathways, which allowed the study of their interaction and the enlightenment of the mechanisms involved in inflammatory lung injury, allowing for the identification of new anti-inflammatory and pro-inflammatory mediators with the potential of becoming interesting pharmacological targets in the modulation of acute lung injury.
Descrição
Tese de doutoramento, Farmácia (Farmacologia e Farmacoterapia), Universidade de Lisboa, Faculdade de Farmácia, 2013
Palavras-chave
Teses de doutoramento - 2013