Caracterização da resposta inflamatória frente à lesão pulmonar aguda murina/ síndrome do desconforto respiratório agudo associado à malária grave
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Data
2013-05-08
Autores
Ortolan, Luana dos Santos [UNIFESP]
Orientadores
Epiphanio, Sabrina [UNIFESP]
Tipo
Dissertação de mestrado
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Malária é um problema de saúde global, especialmente nas regiões tropicais e subtropicais. No Brasil, 99% dos casos concentram-se na Amazônia Legal onde infecções por Plasmodium vivax são as principais causas da doença e podem ser fatais. Infecções por Plasmodium spp. podem levar à um quadro respiratório grave, com complicações pulmonares denominadas lesão pulmonar aguda (ALI) e síndrome do desconforto respiratório agudo (ARDS). As complicações pulmonares são caracterizadas pela diminuição da capacidade de trocas gasosas, aumento da atividade leucocitária e de mediadores inflamatórios nos pulmões. O grande número de fatores potencialmente envolvidos associados às grandes dificuldades no estudo da doença em humanos faz com que as bases moleculares desta disfunção pulmonar permaneçam ainda mal compreendidas, levando a uma alta mortalidade nas unidades de saúde. O objetivo central do presente trabalho foi caracterizar o desenvolvimento das lesões histopatológicas e o processo inflamatório envolvido na patogênese da lesão pulmonar aguda/ síndrome do desconforto respiratório agudo associado à malária grave em um modelo murino. Foi utilizado como modelo experimental a associação entre camundongos da linhagem DBA/2 e o parasita murino Plasmodium berghei ANKA. Neste modelo experimental 23-75% dos camundongos desenvolvem sintomas respiratórios agudos (classificados como ALI/ARDS) enquanto os demais morrem tardiamente (entre 13 e 21 dias após infecção) com sintomas de hiperparasitemia (classificados como HP). As lesões histopatológicas encontradas em camundongos ALI/ARDS incluem a presença de edema, congestão e hemorragia pulmonares, presença de células inflamatórias e membrana hialina. Foi desenvolvido um modelo preditivo baseado no aumento da pausa respiratória (Penh), frequência respiratória e parasitemia, que nos permite classificar os camundongos que desenvolverão ALI/ARDS antes do momento da morte, no 7º dia pós-infecção com alta sensibilidade e especificidade. Nossos resultados principais indicam um aumento da permeabilidade alvéolo-capilar, do heme livre sérico e da carga pararasitária nos pulmões. Verificamos também, um aumento de fatores pró e anti-inflamatórios, tais como IL-10, HO-1, IFN- aumento do influxo de neutrófilos no tecido pulmonar e no lavado broncoalveolar no grupo classificado como ALI/ARDS quando comparado com o grupo HP. Também foi identificada maior área contendo pigmento malárico tanto nos pulmões quanto nos baços de camundongos do grupo ALI/ARDS. Palavras - chave: Malária. ALI/ARDS. Plasmodium berghei. Histopatologia. Neutrófilos.
Malaria is a global health problem, especially in tropical and subtropical regions. In Brazil, 99% of the cases are concentrated in the Amazon Region where infections by Plasmodium vivax are the major cause of morbidity and which can also be fatal. Plasmodium spp. infections can lead to severe respiratory conditions including pulmonary complications named as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Pulmonary complications are characterized by reduced capacity for gas exchange, increased leukocyte activity and inflammatory mediators in the lungs. The molecular basis of pulmonary dysfunction still remains poorly understood because of the large number of factors potentially involved in this disease and the difficulties in the study of this disease in humans, resulting in high mortality in health facilities. The main objective of this study was to characterize the development of histopathological lesions and the inflammatory process involved in the pathogenesis of acute lung injury/ acute respiratory distress syndrome associated with severe malaria in a murine model. We used DBA/2 mice infected with the murine parasite Plasmodium berghei ANKA as the experimental model. In this experimental model 23-75% of mice develop acute respiratory symptoms (classified as ALI / ARDS) while others die later (between 13 and 21 days after infection) with symptoms of hyperparasitemia (classified as HP). Histopathological lesions found in mice with ALI/ ARDS included edema, pulmonary congestion and hemorrhage, the presence of inflammatory cells and hyaline membrane. We developed a mathematical model based on the increase of the respiratory pause (Penh), respiratory rate and parasitemia, which allows us to classify the mice that develop ALI / ARDS before the time of death on day 7 post-infection with high sensitivity and specificity. Our main results indicate increased alveolar-capillary permeability, free heme in the serum and parasite load in the lungs. We also observed increased pro-inflammatory and antiinflammatory factors, such as IL-10, HO-1, IFN- and increased neutrophil influx in the lung tissue and bronchoalveolar lavage in the group classified as ALI/ARDS when compared to the HP group. We also identified increased areas of malarial pigment in both the lungs and the spleens of ALI/ARDS mice.
Malaria is a global health problem, especially in tropical and subtropical regions. In Brazil, 99% of the cases are concentrated in the Amazon Region where infections by Plasmodium vivax are the major cause of morbidity and which can also be fatal. Plasmodium spp. infections can lead to severe respiratory conditions including pulmonary complications named as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Pulmonary complications are characterized by reduced capacity for gas exchange, increased leukocyte activity and inflammatory mediators in the lungs. The molecular basis of pulmonary dysfunction still remains poorly understood because of the large number of factors potentially involved in this disease and the difficulties in the study of this disease in humans, resulting in high mortality in health facilities. The main objective of this study was to characterize the development of histopathological lesions and the inflammatory process involved in the pathogenesis of acute lung injury/ acute respiratory distress syndrome associated with severe malaria in a murine model. We used DBA/2 mice infected with the murine parasite Plasmodium berghei ANKA as the experimental model. In this experimental model 23-75% of mice develop acute respiratory symptoms (classified as ALI / ARDS) while others die later (between 13 and 21 days after infection) with symptoms of hyperparasitemia (classified as HP). Histopathological lesions found in mice with ALI/ ARDS included edema, pulmonary congestion and hemorrhage, the presence of inflammatory cells and hyaline membrane. We developed a mathematical model based on the increase of the respiratory pause (Penh), respiratory rate and parasitemia, which allows us to classify the mice that develop ALI / ARDS before the time of death on day 7 post-infection with high sensitivity and specificity. Our main results indicate increased alveolar-capillary permeability, free heme in the serum and parasite load in the lungs. We also observed increased pro-inflammatory and antiinflammatory factors, such as IL-10, HO-1, IFN- and increased neutrophil influx in the lung tissue and bronchoalveolar lavage in the group classified as ALI/ARDS when compared to the HP group. We also identified increased areas of malarial pigment in both the lungs and the spleens of ALI/ARDS mice.
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Citação
ORTOLAN, Luana dos Santos. Caracterização da resposta inflamatória frente à lesão pulmonar aguda murina/ síndrome do desconforto respiratório agudo associado à malária grave. 2013. 112 f. Dissertação (Mestrado) - Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo (UNIFESP), Diadema, 2013.