Abstract
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.
Highlights
Malaria is one of the most common infectious diseases and is an enormous public-health problem
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
The parasites Plasmodium falciparum and P. berghei ANKA both induced the formation of neutrophil extracellular traps ex vivo
Summary
Malaria is one of the most common infectious diseases and is an enormous public-health problem. Neutrophils are one of the key cells in the pathophysiology of ALI/ARDS driven by various conditions [4] They are recruited to lung tissue where they release reactive oxygen (ROS) and nitrogen species (RNS), cationic proteins, such as myeloperoxidase (MPO); lipid mediators; inflammatory cytokines; elastase and matrix metalloproteinases. These molecules are toxic to invading pathogens, they promote epithelial and endothelial damage [5,6,7,8]. Post-mortem examinations of the lungs of patients with malaria-associated ALI/ARDS have shown the presence of pulmonary edema, inflammatory infiltrates and accumulated inflammatory cells, including neutrophils, in the interstitial and alveolar spaces [11,12]. Evaluating the contribution of neutrophils to malaria associated-ALI/ARDS may help clarify the cellular and molecular mechanisms involved in the pathogenesis of this disease, which is essential for the development of new therapeutic approaches
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