title: Hemozoin induces lung inflammation and correlates with malaria-associated acute respiratory distress syndrome.
abstract: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a deadly complication of malaria, and its pathophysiology is insufficiently understood. Both in humans and in murine models, MA-ARDS is characterized by marked pulmonary inflammation. We investigated the role of hemozoin in MA-ARDS in C57Bl/6 mice infected with Plasmodium berghei NK65, P. berghei ANKA, and P. chabaudi AS. By quantifying hemozoin in the lungs and measuring the disease parameters of MA-ARDS, we demonstrated a highly significant correlation between pulmonary hemozoin concentrations, lung weights, 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 among 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, an increased pulmonary expression of cytokines, chemokines, and enzymes, and concentrations of alveolar vascular endothelial growth factor. The causal relationship between hemozoin and inflammation was investigated by injecting P. falciparum-derived hemozoin intravenously into malaria-free mice. Hemozoin potently induced the pulmonary expression of proinflammatory chemokines (interferon-γ inducible protein-10/CXC-chemokine ligand (CXCL)10, monocyte chemotactic protein-1/CC-chemokine ligand 2, and keratinocyte-derived chemokine/CXCL1), cytokines (IL-1β, IL-6, IL-10, TNF, and transforming growth factor-β), and other inflammatory mediators (inducible nitric oxide synthase, heme oxygenase-1, nicotinamide adenine dinucleotide phosphate- oxidase-2, and intercellular adhesion molecule-1). Thus, hemozoin correlates with MA-ARDS and induces pulmonary inflammation.
authors: Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven–University of Leuven, Leuven 3000, Belgium.
authors: Katrien
authors: K
authors: Deroost
authors: Ariane
authors: A
authors: Tyberghein
authors: Natacha
authors: N
authors: Lays
authors: Sam
authors: S
authors: Noppen
authors: Evelin
authors: E
authors: Schwarzer
authors: Els
authors: E
authors: Vanstreels
authors: Mina
authors: M
authors: Komuta
authors: Mauro
authors: M
authors: Prato
authors: Jing-Wen
authors: JW
authors: Lin
authors: Ana
authors: A
authors: Pamplona
authors: Chris J
authors: CJ
authors: Janse
authors: Paolo
authors: P
authors: Arese
authors: Tania
authors: T
authors: Roskams
authors: Dirk
authors: D
authors: Daelemans
authors: Ghislain
authors: G
authors: Opdenakker
authors: Philippe E
authors: PE
authors: Van den Steen
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018791:CD4 Lymphocyte Count; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D015870:Gene Expression; D006420:Hemeproteins / Q000378:metabolism* / Q000502:physiology; D006790:Host-Parasite Interactions; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D008264:Macrophages / Q000378:metabolism / Q000469:parasitology; D008288:Malaria / Q000150:complications / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010962:Plasmodium berghei / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D016788:Plasmodium chabaudi / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000378:metabolism*; D052939:Schizonts / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D006420:Hemeproteins; C556062:IL10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016753:Interleukin-10; C020753:hemozoin