Impaired host defense and increased inflammation in mice deficient in myeloperoxidase and NADPH-oxidase
| Project/Area Number |
16580243
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Basic veterinary science/Basic zootechnical science
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| Research Institution | Yokohama City University |
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Principal Investigator |
ARATANI Yasuaki Yokohama City University, Kihara Institute for Biological Research, Associate Professor, 木原生物学研究所, 準教授 (30192470)
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| Co-Investigator(Kenkyū-buntansha) |
KOYAMA Hideki Yokohama City University, Kihara Institute for Biological Research, Professor, 教授 (40085626)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | neutrophil / reactive oxygen species / infection / inflammation / apoptosis |
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| Research Abstract |
The first study investigated the role of myeloperoxidase (MPO) in defense against Cryptococcus neoformans in a MPO-deficient (MPO-KO) mouse model. The survival of MPO-KO mice infected with C.neoformans was lower than that wild-type. The MPO-KO mice had significantly larger lung fungal burdens than wild-type mice. On day 7,MPO-KO mice showed a weak Th1 response to C.neoformans. The MPO-KO mice showed more severe pneumonia than wild-type, which was associated with the increase in the levels of IL-1α/β in the lungs. In MPO-KO mice, the pulmonary infection disseminated to the brain with occasional meningitis. KC level in the brain of infected MPO-KO mice was higher than that of control mice. These data suggest a major role of MPO in the response to cryptococcal infection.
The second study examined the role of neutrophil-derived ROS in neutrophil recruitment into ultraviolet B (UVB)-exposed skin of mice. UVB exposure of mice deficient in MPO, NADPH oxidase, or both, caused skin neutrophil in
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filtration peaking at 60, 48, and 48 h, respectively, which was earlier than the 72-h peak in wild-type mice. MIP-2 level was higher in mutant than wild-type. Neutrophil migration toward a localized source of KC was higher in mutant than wild-type. These results suggest that ROS produced by neutrophils regulate expression of MIP-2 and migration of neutrophils toward KC. This may explain the earlier infiltration of mutant neutrophils in response to UVB.
Stimulation of normal mouse neutrophils with phorbol 12-myristate 13-acetate (PMA) resulted in an acceleration of chromatin condensation and phosphatidylserine externalization that was not associated with caspase-3 activation. Caspase-independent death was completely inhibited by specific inhibitors for protein kinase C and p38 mitogen-activated protein kinase (p38MAPK), respectively. Activation of p38 MAPK is regulated by protein kinase C. On the other hand, cell death was abolished in NADPH oxidase-deficient neutrophils. p38 MAPK was activated by PMA in normal and MPO-KO neutrophils, whereas no activation was observed in NADPH oxidase-deficient neutrophils. These results strongly suggest that activation of p38 MAPK is regulated by endogenously generated superoxide or its metabolites other than HOCl. Less
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Report
(3 results)
Research Products
(18 results)
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[Journal Article] Contribution of the myeloperoxidase-dependent oxidative system to host defense against Cryptococcus neoformans.2006
Author(s)
Aratani, Y., Kura, F., Watanabe, H., Akagawa, H., Takano, Y., Ishida-Okawara, A., Suzuki, K., Maeda, N., Koyama, H
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Journal Title
J.Med.Microbiol. (in press)
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Pregnancy Promotes Myeloperoxidase Accumulation at the Cell Surface and Enhances Cell Metabolism and Oxidant Release by Maternal Neutrophils.2006
Author(s)
Kindzelskii, A.L., Clark, A.J., Espinoza, J., Maeda, N., Aratani, Y., Romero, R., Petty, A.R
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Journal Title
Eur.J.Immunol. 10
Pages: 1619-1628
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Interferon-g Primes RAW264 Macrophages and Human Monocytes for Enhanced Oxidant Production in Response to CpG DNA via Metabolic Signaling : Roles of TLR9 and Myeloperoxidase Trafficking.2006
Author(s)
Adachi, Y, Kindzelskii, A.L., Petty, A.R., Huang, J., Maeda, N., Aratani, Y., Ohno, K., Petty, A.R
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Journal Title
J.Immunol. 176
Pages: 5033-5040
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] In vivo role of myeloperoxidase for the host defense.2004
Author(s)
Aratani, Y., Kura, F., Watanabe, H., Akagawa, H., Takano, Y., Suzuki, K., Dinauer, M.C., Maeda, N., Koyama, H
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Journal Title
Description
「研究成果報告書概要(欧文)」より
Related Report
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