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

Author(s):Show less -

Sercundes, Michelle K. ; Ortolan, Luana S. ; Debone, Daniela ; Soeiro-Pereira, Paulo V. ; Gomes, Eliane ; Aitken, Elizabeth H. ; Neto, Antonio Condino ; Russo, Momtchilo ; D' Imperio Lima, Maria R. ; Alvarez, Jose M. ; Portugal, Silvia ; Marinho, Claudio R. F. ; Epiphanio, Sabrina

• Document type: Journal article
• Source: PLOS PATHOGENS; v. 12, n. 12 DEC 2016.
• Web of Science Citations: 23

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. (AU)

• FAPESP's process: 09/53256-7 - Distress syndrome in a murine model associated to the severe malaria: a study of parasite-host interaction
• Grantee: Sabrina Epiphanio
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 13/20718-3 - The role of cytoadherence and Toll-like receptors (TLRs) in the immunopathogenesis of murine severe malaria associated acute respiratory distress syndrome
• Grantee: Luana dos Santos Ortolan
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 11/19525-0 - Malaria associated acute lung injury and acute respiratory distress syndrome through in vitro and in vivo models
• Grantee: Elizabeth Helen Aitken
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 10/11925-7 - Identification e characterization of acute respiratory distress syndrome in a murine model associated to the severe malaria: study of parasite-host interaction
• Grantee: Sabrina Epiphanio
• Support type: Research Grants - Visiting Researcher Grant - International
• FAPESP's process: 09/53889-0 - Study of the immunopathological mechanisms involved in pregnancy-associated malaria
• Grantee: Cláudio Romero Farias Marinho
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 10/19439-4 - Assessment of the immunopathological mechanisms involved in malaria-associated acute lung injury
• Grantee: Michelle Klein Sercundes
• Support type: Scholarships in Brazil - Doctorate