Association of Heme Oxygenase 1 with Lung Protection in Malaria-Associated ALI/ARDS

Abstract

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.

Physiopathology of Malaria-Associated Acute Respiratory Distress Syndrome

“…This adhesion allows the parasite complete its life cycle without being eliminated by hemocathesis, thus increasing the severity of disease [5]. However, in MA-ARDS it is not very clear which adhesion molecule is responsible for the interaction of iRBC with pulmonary vascular endothelium [11,24,31].…”

Avaliação do citoesqueleto e da barreira endotelial pulmonar na malária experimental

“…Além disso, em 2016, nosso grupo de pesquisa demonstrou que a indução da heme-oxigenase-1 (enzima com atividade anti-inflamatória e anti-apoptótica), a partir do tratamento com hemina, em células endoteliais primárias pulmonares de camundongos DBA/2 (CEPP-DBA/2) estimuladas com lisado P. berghei ANKA, reduz a permeabilidade vascular, indicando a ação protetora desta droga sobre os efeitos lesivos no endotélio microvascular dos pulmões, causados pelo lisado do parasita (PEREIRA et al, 2016). …”

Estudo da permeabilidade vascular pulmonar e das junções interendoteliais na malária experimental

“…Os achados anatomopatológicos e histopatológicos evidenciaram que a presença de efusão pleural e o aumento da permeabilidade vascular pulmonar, associados ao edema e às hemorragias alveolares graves, que culminaram na morte dos camundongos por insuficiência respiratória. Entretanto, os camundongos que não desenvolvem a SDRA apresentam um quadro de hiperparasitemia (HP) caracterizado pela anemia severa e contagem alta de eritrócitos parasitados no sangue periférico e a ausência de efusão pleural (EPIPHANIO et al, 2010;AITKEN et al, 2014;ORTOLAN et al, 2014;PEREIRA et al, 2016;SERCUNDES et al, 2016). Para melhor compreensão dos mecanismos envolvidos no aumento da permeabilidade vascular é importante a utilização dos estudos in vitro com células endoteliais estimuladas com o Plasmodium, para avaliar o envolvimento das proteínas constituintes nas junções interendoteliais neste mecanismo (SUSOMBOON et al, 2006;GILLRIE et al, 2007GILLRIE et al, , 2012).…”