Delayed mortality and attenuated thrombocytopenia associated with severe malaria in urokinase- and urokinase receptor-deficient mice

被引:55
作者
Piguet, PF
Da Laperrousaz, C
Vesin, C
Tacchini-Cottier, F
Senaldi, G
Grau, GE
机构
[1] Univ Geneva, Dept Pathol, CH-1211 Geneva, Switzerland
[2] WHO, IRTC, CH-1066 Epalinges, Switzerland
[3] Amgen Inc, Thousand Oaks, CA 91320 USA
[4] Univ Mediterranee, CNRS UPRES A6020, F-13385 Marseille, France
关键词
D O I
10.1128/IAI.68.7.3822-3829.2000
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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收藏
页码:3822 / 3829
页数:8
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