title: Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice.
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.
authors.affiliation: Instituto de Medicina Tropical de São Paulo, Universidade de São Paulo, São Paulo, Brazil.|Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Sercundes
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Luana S
authors.identifier: 0000-0003-1153-9987
authors.initials: LS
authors.lastname: Ortolan
authors.affiliation: Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Daniela
authors.identifier: 0000-0001-5316-5130
authors.initials: D
authors.lastname: Debone
authors.affiliation: Departamento de Patologia, Universidade Federal do Maranhão, Maranhão, Brazil.
authors.forename: Paulo V
authors.initials: PV
authors.lastname: Soeiro-Pereira
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Eliane
authors.initials: E
authors.lastname: Gomes
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Elizabeth H
authors.identifier: 0000-0002-2677-6208
authors.initials: EH
authors.lastname: Aitken
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Antonio
authors.initials: A
authors.lastname: Condino-Neto
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Momtchilo
authors.identifier: 0000-0003-3553-3184
authors.initials: M
authors.lastname: Russo
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Maria R
authors.initials: MR
authors.lastname: D' Império Lima
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: José M
authors.initials: JM
authors.lastname: Alvarez
authors.affiliation: Center of Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Portugal
authors.affiliation: Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Claudio R F
authors.identifier: 0000-0002-1227-3845
authors.initials: CR
authors.lastname: Marinho
authors.affiliation: Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Epiphanio
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology* / Q000382:microbiology; D000818:Animals; D004195:Disease Models, Animal; D065206:Extracellular Traps / Q000276:immunology; D005455:Fluorescent Antibody Technique; D008288:Malaria / Q000150:complications / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009504:Neutrophils / Q000276:immunology*; D016133:Polymerase Chain Reaction; D012128:Respiratory Distress Syndrome / Q000276:immunology* / Q000382:microbiology