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    Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice

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    Author
    Sercundes, MK; Ortolan, LS; Debone, D; Soeiro-Pereira, PV; Gomes, E; Aitken, EH; Neto, AC; Russo, M; D' Imperio Lima, MR; Alvarez, JM; ...
    Date
    2016-12-01
    Source Title
    PLoS Pathogens
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Aitken, Elizabeth
    Affiliation
    Medicine and Radiology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Sercundes, M. K., Ortolan, L. S., Debone, D., Soeiro-Pereira, P. V., Gomes, E., Aitken, E. H., Neto, A. C., Russo, M., D' Imperio Lima, M. R., Alvarez, J. M., Portugal, S., Marinho, C. R. F. & Epiphanio, S. (2016). Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice. PLOS PATHOGENS, 12 (12), https://doi.org/10.1371/journal.ppat.1006054.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255483
    DOI
    10.1371/journal.ppat.1006054
    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.

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