Malaria remains one of the greatest burdens to global health, causing nearly 500,000 deaths in 2014. When manifesting in the lungs, severe malaria causes acute lung injury/acute respiratory distress syndrome (ALI/ARDS). We have previously shown that a proportion of DBA/2 mice infected with Plasmodium berghei ANKA (PbA) develop ALI/ARDS and that these mice recapitulate various aspects of the human syndrome, such as pulmonary edema, hemorrhaging, pleural effusion and hypoxemia. Herein, we investigated the role of neutrophils in the pathogenesis of malaria-associated ALI/ARDS. Mice developing ALI/ARDS showed greater neutrophil accumulation in the lungs compared with mice that did not develop pulmonary complications. In addition, mice with ALI/ARDS produced more neutrophil-attracting chemokines, myeloperoxidase and reactive oxygen species. We also observed that the parasites Plasmodium falciparum and PbA induced the formation of neutrophil extracellular traps (NETs) ex vivo, which were associated with inflammation and tissue injury. The depletion of neutrophils, treatment with AMD3100 (a CXCR4 antagonist), Pulmozyme (human recombinant DNase) or Sivelestat (inhibitor of neutrophil elastase) decreased the development of malaria-associated ALI/ARDS and significantly increased mouse survival. This study implicates neutrophils and NETs in the genesis of experimentally induced malaria-associated ALI/ARDS and proposes a new therapeutic approach to improve the prognosis of severe malaria. A deeper understanding of the pathogenesis of malaria-associated ALI/ARDS may help in the development of new therapeutic approaches to improve the prognosis of severe cases of malaria. Using the Plasmodium berghei ANKA-infection mouse model of ALI/ARDS, which resembles the human disease in many aspects, this study reports the critical role of neutrophils in the pathogenesis of this syndrome. Mice developing ALI/ARDS showed abundant lung-infiltrating neutrophils in association with the increased production of neutrophil-attracting chemokines, myeloperoxidase and reactive oxygen species. The parasites Plasmodium falciparum and P. berghei ANKA both induced the formation of neutrophil extracellular traps ex vivo. By targeting neutrophils and neutrophil extracellular traps with specific drugs, we succeeded in preventing the development of malaria-associated ALI/ARDS and significantly increased mouse survival.

The COVID-19 pandemic has imposed a unique situation for humanity, reaching up to 5623 deaths in Sao Paulo city during the analyzed period of this study. Due to the measures for social distancing, an improvement of air quality was observed worldwide. In view of this scenario, we investigated the air quality improvement related to PM₁₀, PM_2.5, and NO₂ concentrations during 90 days of quarantine compared to an equivalent period in 2019. We found a significant drop in air pollution of 45% of PM₁₀, 46% of PM_2.5, and 58% of NO₂, and using a relative-risk function, we estimated that this significant air quality improvement avoided, respectively, 78, 337, and 387 premature deaths, respectively, and prevented approximately US $720 million on health costs. Moreover, we estimated that 5623 deaths by COVID-19 represent an economic health loss of US $10.5 billion. Both health and economic gains associated with air pollution reductions give a positive perspective of the efforts towards keeping air pollution reduced even after the pandemic, highlighting the importance of improving the strategies of air pollution mitigation actions, as well as the crucial role of adopting efficient measures to protect human health both during and after the COVID-19 global health crisis.

Malaria is a serious disease, caused by the parasite of the genusPlasmodium, 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 withPlasmodium bergheiANKA. 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.

Malaria-associated acute lung injury/acute respiratory distress syndrome (ALI/ARDS) often results in morbidity and mortality. Murine models to study malaria-associated ALI/ARDS have been described; we still lack a method of distinguishing which mice will develop ALI/ARDS before death. This work aimed to characterize malaria-associated ALI/ARDS in a murine model and to demonstrate the first method to predict whether mice are suffering from ALI/ARDS before death. DBA/2 mice infected withPlasmodium bergheiANKA developing ALI/ARDS or hyperparasitemia (HP) were compared using histopathology, PaO₂measurement, pulmonary X-ray, breathing capacity, lung permeability, and serum vascular endothelial growth factor (VEGF) levels according to either the day of death or the suggested predictive criteria. We proposed a model to predict malaria-associated ALI/ARDS using breathing patterns (enhanced pause and frequency respiration) and parasitemia as predictive criteria from mice whose cause of death was known to retrospectively diagnose the sacrificed mice as likely to die of ALI/ARDS as early as 7 days after infection. Using this method, we showed increased VEGF levels and increased lung permeability in mice predicted to die of ALI/ARDS. This proposed method for accurately identifying mice suffering from ALI/ARDS before death will enable the use of this model to study the pathogenesis of this disease.