title: Parasite burden and CD36-mediated sequestration are determinants of acute lung injury in an experimental malaria model.
abstract: Although acute lung injury (ALI) is a common complication of severe malaria, little is known about the underlying molecular basis of lung dysfunction. Animal models have provided powerful insights into the pathogenesis of severe malaria syndromes such as cerebral malaria (CM); however, no model of malaria-induced lung injury has been definitively established. This study used bronchoalveolar lavage (BAL), histopathology and gene expression analysis to examine the development of ALI in mice infected with Plasmodium berghei ANKA (PbA). BAL fluid of PbA-infected C57BL/6 mice revealed a significant increase in IgM and total protein prior to the development of CM, indicating disruption of the alveolar-capillary membrane barrier-the physiological hallmark of ALI. In contrast to sepsis-induced ALI, BAL fluid cell counts remained constant with no infiltration of neutrophils. Histopathology showed septal inflammation without cellular transmigration into the alveolar spaces. Microarray analysis of lung tissue from PbA-infected mice identified a significant up-regulation of expressed genes associated with the gene ontology categories of defense and immune response. Severity of malaria-induced ALI varied in a panel of inbred mouse strains, and development of ALI correlated with peripheral parasite burden but not CM susceptibility. Cd36(-/-) mice, which have decreased parasite lung sequestration, were relatively protected from ALI. In summary, parasite burden and CD36-mediated sequestration in the lung are primary determinants of ALI in experimental murine malaria. Furthermore, differential susceptibility of mouse strains to malaria-induced ALI and CM suggests that distinct genetic determinants may regulate susceptibility to these two important causes of malaria-associated morbidity and mortality.
authors.affiliation: Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Lovegrove
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.forename: Lourdes
authors.initials: L
authors.lastname: Peña-Castillo
authors.forename: Samir N
authors.initials: SN
authors.lastname: Patel
authors.forename: John T
authors.initials: JT
authors.lastname: Ruzinski
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006790:Host-Parasite Interactions; D008168:Lung / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D016779:Malaria, Cerebral / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010962:Plasmodium berghei / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013045:Species Specificity
chemical_list: D018955:CD36 Antigens; D016207:Cytokines; D012333:RNA, Messenger