Immunopathology and Dexamethasone Therapy in a New Model for Malaria-Associated Acute Respiratory Distress Syndrome.

Am J Respir Crit Care Med. 2010 Jan 21;

Authors: Van den Steen PE, Geurts N, Deroost K, Van Aelst I, Verhenne S, Heremans H, Van Damme J, Opdenakker G

RATIONALE: Malaria infection is often complicated by malaria-associated acute respiratory distress syndrome (MA-ARDS), characterized by pulmonary edema and hemorrhages. No efficient treatments are available for MA-ARDS and its pathogenesis remains poorly understood. OBJECTIVES: Development of a new animal model for MA-ARDS to explore the pathogenesis and possible treatments. METHODS: C57Bl/6 mice were infected with Plasmodium berghei NK65, and the development of MA-ARDS was evaluated by the analysis of lung weight, histopathology and broncho-alveolar lavages. Cytokine and chemokine expression in the lungs was analyzed by RT-PCR, and the accumulation of leukocyte subclasses was determined by FACS analysis. MEASUREMENTS AND MAIN RESULTS: In this model, the pulmonary expression of several cytokines and chemokines was increased to a higher level than in mice infected with P. chabaudi AS, which does not cause MA-ARDS. By depletion experiments, CD8(+) T lymphocytes were shown to be pathogenic. High doses of dexamethasone blocked MA-ARDS, even when given after appearance of the lung complications, and reduced pulmonary leukocyte accumulation and the expression of a monocyte/macrophage-attracting chemokine. CONCLUSIONS: We developed a novel model of MA-ARDS with many similarities to human MA-ARDS and without cerebral complications. This contrasts with the more classical model with P. berghei ANKA, characterized by fulminant cerebral malaria. Hence, infection with P. berghei NK65 generates a broader time window to study the pathogenesis and to evaluate candidate treatments. The finding that high doses of dexamethasone cured MA-ARDS suggests that it might be more effective against MA-ARDS than it was in the clinical trials for cerebral malaria.

PMID: 20093644 [PubMed - as supplied by publisher]