Delayed mortality and attenuated thrombocytopenia associated with severe malaria in urokinase- and urokinase receptor-deficient mice.
We explored the role of urokinase and tissue-type plasminogen activators (uPA and tPA), as well as the uPA receptor (uPAR; CD87) in mouse severe malaria (SM), using genetically deficient (-/-) mice. The mortality resulting from Plasmodium berghei ANKA infection was delayed in uPA(-/-) and uPAR(-/-) mice but was similar to that of the wild type (+/+) in tPA(-/-) mice. Parasitemia levels were similar in uPA(-/-), uPAR(-/-), and +/+ mice. Production of tumor necrosis factor, as judged from the plasma level and the mRNA levels in brain and lung, was markedly increased by infection in both +/+ and uPAR(-/-) mice. Breakdown of the blood-brain barrier, as evidenced by the leakage of Evans Blue, was similar in +/+ and uPAR(-/-) mice. SM was associated with a profound thrombocytopenia, which was attenuated in uPA(-/-) and uPAR(-/-) mice. Administration of aprotinin, a plasmin antagonist, also delayed mortality and attenuated thrombocytopenia. Platelet trapping in cerebral venules or alveolar capillaries was evident in +/+ mice but absent in uPAR(-/-) mice. In contrast, macrophage sequestration in cerebral venules or alveolar capillaries was evident in both +/+ and uPAR(-/-) mice. Polymorphonuclear leukocyte sequestration in alveolar capillaries was similar in +/+ and uPAR(-/-) mice. These results demonstrate that the uPAR deficiency attenuates the severity of SM, probably by its important role in platelet kinetics and trapping. These results therefore suggest that platelet sequestration contributes to the pathogenesis of SM.
Piguet
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PF
Department of Pathology, University of Geneva, Geneva CH 1211, Switzerland. pierre.piguet@medecine.unige.ch
Da Laperrousaz
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Vesin
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Tacchini-Cottier
F
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Senaldi
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Grau
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GE
D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D001792:Blood Platelets / Q000473:pathology; D001812:Blood-Brain Barrier; D002470:Cell Survival; D005340:Fibrinogen / Q000378:metabolism; D007700:Kinetics; D008168:Lung / Q000473:pathology; D008288:Malaria / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D018512:Parasitemia / Q000150:complications / Q000235:genetics / Q000378:metabolism; D010962:Plasmodium berghei; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D013154:Spleen / Q000473:pathology; D013921:Thrombocytopenia / Q000209:etiology; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency* / Q000235:genetics
C524899:Plaur protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; D007611:Aprotinin; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator