RESUMO
Annually, many pregnancies occur in areas of Plasmodium spp. transmission, particularly in underdeveloped countries with widespread poverty. Estimations have suggested that several million women are at risk of developing malaria during pregnancy. In particular cases, systemic infection caused by Plasmodium spp. may extend to the placenta, dysregulating local homeostasis and promoting the onset of placental malaria; these processes are often associated with increased maternal and fetal mortality, intrauterine growth restriction, preterm delivery, and reduced birth weight. The endeavor to understand and characterize the mechanisms underlying disease onset and placental pathology face several ethical and logistical obstacles due to explicit difficulties in assessing human gestation and biological material. Consequently, the advent of murine experimental models for the study of malaria during pregnancy has substantially contributed to our understanding of this complex pathology. Herein, we summarize research conducted during recent decades using murine models of malaria during pregnancy and highlight the most relevant findings, as well as discuss similarities to humans and the translational capacity of achieved results.
RESUMO
Malaria is a serious disease and was responsible for 429,000 deaths in 2015. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications of severe malaria; it is characterized by a high mortality rate and can even occur after antimalarial treatment when parasitemia is not detected. Rodent models of ALI/ARDS show similar clinical signs as in humans when the rodents are infected with murine Plasmodium. In these models, it was shown that the induction of the enzyme heme oxygenase 1 (HO-1) is protective against severe malaria complications, including cerebral malaria and ALI/ARDS. Increased lung endothelial permeability and upregulation of VEGF and other pro-inflammatory cytokines were found to be associated with malaria-associated ALI/ARDS (MA-ALI/ARDS), and both were reduced after HO-1 induction. Additionally, mice were protected against MA-ALI/ARDS after treatment with carbon monoxide- releasing molecules or with carbon monoxide, which is also released by the HO-1 activity. However, high HO-1 levels in inflammatory cells were associated with the respiratory burst of neutrophils and with an intensification of inflammation during episodes of severe malaria in humans. Here, we review the main aspects of HO-1 in malaria and ALI/ARDS, presenting the dual role of HO-1 and possibilities for therapeutic intervention by modulating this important enzyme.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Heme Oxigenase-1/farmacologia , Heme Oxigenase-1/uso terapêutico , Malária/tratamento farmacológico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Permeabilidade Capilar , Monóxido de Carbono/farmacologia , Monóxido de Carbono/uso terapêutico , Citocinas/metabolismo , Modelos Animais de Doenças , Endotélio , Humanos , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Malária/complicações , Proteínas de Membrana , Camundongos , Neutrófilos , Plasmodium/patogenicidade , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/prevenção & controle , RoedoresRESUMO
Malaria is a serious disease, caused by the parasite of the genus Plasmodium, which was responsible for 440,000 deaths in 2015. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications in severe malaria. The murine model DBA/2 reproduces the clinical signs of ALI/ARDS in humans, when infected with Plasmodium berghei ANKA. High levels of HO-1 were reported in cases of severe malaria. Our data indicated that the HO-1 mRNA and protein expression are increased in mice that develop malaria-associated ALI/ARDS (MA-ALI/ARDS). Additionally, the hemin, a HO-1 inducing drug, prevented mice from developing MA-ALI/ARDS when administered prior to the development of MA-ALI/ARDS in this model. Also, hemin treatment showed an amelioration of respiratory parameters in mice, high VEGF levels in the sera, and a decrease in vascular permeability in the lung, which are signs of ALI/ARDS. Therefore, the induction of HO-1 before the development of MA-ALI/ARDS could be protective. However, the increased expression of HO-1 on the onset of MA-ALI/ARDS development may represent an effort to revert the phenotype of this syndrome by the host. We therefore confirm that HO-1 inducing drugs could be used for prevention of MA-ALI/ARDS in humans.