Immunopathology and dexamethasone therapy in a new model for malaria-associated acute respiratory distress syndrome.
BACKGROUND
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.


OBJECTIVE
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 bronchoalveolar lavages. Cytokine and chemokine expression in the lungs was analyzed by reverse transcription-polymerase chain reaction, and the accumulation of leukocyte subclasses was determined by flow cytometric analysis.


RESULTS
In this model, the pulmonary expression of several cytokines and chemokines was increased to a higher level than in mice infected with Plasmodium 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 administered after appearance of the complication, 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.
Van den Steen
Philippe E
PE
Laboratory of Immunobiology, Rega Institute for Medical Research, Catholic University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. philippe.vandensteen@rega.kuleuven.be
Geurts
Nathalie
N
Deroost
Katrien
K
Van Aelst
Ilse
I
Verhenne
Sebastien
S
Heremans
Hubertine
H
Van Damme
Jo
J
Opdenakker
Ghislain
G
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004487:Edema / Q000209:etiology; D006470:Hemorrhage / Q000209:etiology; D034141:Hypoalbuminemia / Q000209:etiology; D008168:Lung / Q000473:pathology; D018655:Lymphocyte Count; D008264:Macrophages / Q000473:pathology; D008288:Malaria / Q000150:complications*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
D018925:Chemokines; D016207:Cytokines; D003907:Dexamethasone