Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a deadly complication and its pathophysiology is insufficiently understood. Both in humans and mouse models, MA-ARDS is characterized by marked pulmonary inflammation. We investigated the role of hemozoin in MA-ARDS in C57Bl/6 mice infected with P. berghei NK65, P. berghei ANKA and P. chabaudi AS. By quantifying hemozoin in the lungs and measuring disease parameters of MA-ARDS, we demonstrate a highly significant correlation between pulmonary hemozoin levels, lung weight and alveolar edema. Histological analysis of the lungs demonstrated that hemozoin is localized in phagocytes and infected erythrocytes, and only occasionally in granulocytes. Species-specific differences in hemozoin production, as measured in individual schizonts, were associated with variations in pulmonary pathogenicity. Furthermore, both pulmonary hemozoin and lung pathology were correlated with the number of infiltrating inflammatory cells, increased pulmonary expression of cytokines, chemokines and enzymes, and alveolar VEGF levels. The causal relation between hemozoin and inflammation was investigated by injecting P. falciparumderived hemozoin intravenously in malaria-free mice. Hemozoin potently induced the pulmonary expression of pro-inflammatory chemokines (IP-10/CXCL10, MCP-1/CCL2, and KC/CXCL1), cytokines (IL-1β, IL-6, IL-10, TNF, and TGF-β) and other inflammatory mediators (iNOS, Hmox1, NOX2, and ICAM- 1). Thus, hemozoin correlates with MA-ARDS and induces pulmonary inflammation.
Hemozoin is a Prominent Inflammatory Virulence Factor in Malaria-Associated Acute Respiratory Distress Syndrome
KEILING, BRIGITTE EVELIN;PRATO, Mauro;ARESE, Paolo;
2012-01-01
Abstract
Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a deadly complication and its pathophysiology is insufficiently understood. Both in humans and mouse models, MA-ARDS is characterized by marked pulmonary inflammation. We investigated the role of hemozoin in MA-ARDS in C57Bl/6 mice infected with P. berghei NK65, P. berghei ANKA and P. chabaudi AS. By quantifying hemozoin in the lungs and measuring disease parameters of MA-ARDS, we demonstrate a highly significant correlation between pulmonary hemozoin levels, lung weight and alveolar edema. Histological analysis of the lungs demonstrated that hemozoin is localized in phagocytes and infected erythrocytes, and only occasionally in granulocytes. Species-specific differences in hemozoin production, as measured in individual schizonts, were associated with variations in pulmonary pathogenicity. Furthermore, both pulmonary hemozoin and lung pathology were correlated with the number of infiltrating inflammatory cells, increased pulmonary expression of cytokines, chemokines and enzymes, and alveolar VEGF levels. The causal relation between hemozoin and inflammation was investigated by injecting P. falciparumderived hemozoin intravenously in malaria-free mice. Hemozoin potently induced the pulmonary expression of pro-inflammatory chemokines (IP-10/CXCL10, MCP-1/CCL2, and KC/CXCL1), cytokines (IL-1β, IL-6, IL-10, TNF, and TGF-β) and other inflammatory mediators (iNOS, Hmox1, NOX2, and ICAM- 1). Thus, hemozoin correlates with MA-ARDS and induces pulmonary inflammation.
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