Experiments with mice conducted at USP (University of São Paulo) revealed one of the mechanisms that lead to acute respiratory distress syndrome (ARDS) caused by malaria. This type of complication has no early diagnosis and mortality reaches 80% of affected patients.
The study, published in the journal Cell Death & Disease, also showed that intervention in this process can reduce mortality, thus opening a path for work that seeks new treatments in humans.
The tests were done with mice known as DBA/2 infected with the Plasmodium berghei ANKA parasite. The model mimics several aspects of the human syndrome, such as pulmonary edema, hemorrhages, pleural effusion and insufficient oxygen in the blood (hypoxemia).
In the article, the scientists describe that apoptosis (a kind of programmed cell death) contributes to the development of the syndrome by facilitating the breakdown of the alveolar-capillary barrier in the lungs, where carbon dioxide is exchanged for oxygen.
This is because, after apoptosis, there is an increase in vascular permeability caused by the contact of the infected erythrocyte (red blood cell) with the cells that line the blood vessels (endothelial). These cells separate and enlarge the “holes” between them, thus allowing the passage of fluid to the extravascular environment and causing pulmonary edema.
Mice with ARDS showed a greater amount of apoptosis in both endothelial and inflammatory cells (leukocytes) when compared to animals that did not develop the syndrome and to those not infected by Plasmodium (control group).
According to the research, caspases (a family of proteins that regulate cell death and inflammation processes) are responsible for the mechanisms of cell death. When treated with a caspase inhibitor, ZVAD-fmk, the group observed a reduction in apoptosis and a decrease in edema formation. As a result, there was a drop in the mortality of sick animals — they had improved respiratory capacity and lung lesions.
“In addition to having contributed to the understanding of one of the mechanisms that lead to acute respiratory distress syndrome and increased vascular permeability, we have shown that intervening in this process can contribute to reducing mortality in malaria cases, which is quite high,” summarizes to Agência Fapesp Sabrina Epiphanio, professor at the Faculty of Pharmaceutical Sciences at USP and supervisor of the study.
The first authors of the article, Michelle Klein Sercundes and Luana dos Santos Ortolan, were Epiphanio’s graduate students (master’s, doctoral and post-doctoral). The group, which also includes researchers from the Institute of Biomedical Sciences (ICB-USP) and the Federal University of ABC (UFABC), received support from Fapesp through five projects (13/20718-3, 15/06106-0, 20 /06747-4, 20/03175-0 and 20/03163-1).
“There are not many in vivo studies on this type of respiratory syndrome. Few groups work in this line, hence the originality of the results obtained”, says Epiphanio, who has studied the subject for almost 15 years (read more at: agencia.fapesp.br/ 12124/).
Malaria-associated ARDS is a serious illness that affects between 5% and 20% of people infected with Plasmodium, of which about 80% die even when undergoing hospital treatment with intensive care. The pathogenesis of the disease, that is, the way it affects the organism, is still little explored and there are no tests to detect the problem early. There are still difficulties of study in humans.
new cases
“The acute respiratory syndrome caused by malaria is similar to that of Covid-19”, explains the professor.
Because of the pandemic, malaria prevention, diagnosis and treatment programs in several countries were interrupted, resulting in an increase in cases and deaths between 2019 and 2020. WHO (World Health Organization) report pointed to 14 million new malaria records and 69,000 deaths, two thirds of the deaths resulting from these suspensions.
Present in 97 countries, considered endemic areas, the disease puts 40% of the world population at risk. In Brazil, 99% of malaria cases are concentrated in the Amazon region. In 2020, there were more than 140,000 autochthonous records in the country, of which 80% were confirmed in 37 municipalities, according to a report by the Ministry of Health. In the period, there were 42 deaths.
Considered one of the infectious diseases that most affect humanity, malaria has Plasmodium as the causative agent, with five different types of the protozoan being known. The most prevalent are falciparum — which is more aggressive and for which a vaccine was recently approved — and vivax, which accounts for 84% of registrations in Brazil. All can lead the patient to develop ARDS.
Transmission occurs through the bite of the female Anopheles mosquito, when infected. And the clinical manifestations are high fever, chills, tremors, sweating and headache. There are people who also experience nausea, vomiting, tiredness and lack of appetite. The treatment is done with antimalarial drugs, provided by the Unified Health System (SUS), which prevent the development of the parasite.
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