Clinical and serologic manifestations of autoimmune disease in MRL-lpr/lpr mice lacking nitric oxide synthase type 2.
Clinical and serologic manifestations of autoimmune disease in MRL-lpr/lpr mice lacking nitric oxide synthase type 2.
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DOI：
10.1084/jem.186.3.365
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发表时间：
1997-08-04
影响因子：
15.3
通讯作者：
Weinberg, JB
中科院分区：
文献类型：
--
作者：
Gilkeson, GS;Mudgett, JS;Seldin, MF;Ruiz, P;Alexander, AA;Misukonis, MA;Pisetsky, DS;Weinberg, JB
一氧化氮（NO）是炎症反应的重要介质。MRL-lpr/lpr小鼠过表达诱导型一氧化氮合酶（NOS 2）和过量产生NO的发展与自身免疫综合征的各种炎症表现平行。在以前的研究中，我们发现，抑制NO的产生与非选择性一氧化氮合酶（NOS）抑制剂NG-单甲基精氨酸减少肾小球肾炎，关节炎，血管炎的MRL-lpr/lpr小鼠。为了进一步确定NO和NOS 2在MRL-1 pr/1 pr小鼠疾病中的作用，通过同源重组产生具有NOS 2靶向破坏的小鼠，并将其与MRL-1 pr/1 pr小鼠繁殖至N4代。本研究使用了MRL-lpr/lpr同窝出生的NOS 2破坏纯合子（−/−）、NOS 2破坏杂合子（+/−）或野生型（+/+）。与MRL-lpr/lpr（+/+）小鼠相比，MRL-lpr/lpr（-/-）小鼠的NO产生量显着减少，MRL-lpr/lpr（+/-）小鼠的NO产生量居中。通过免疫印迹分析，在（−/−）动物的脾、肝、肾和腹腔巨噬细胞中未检测到NOS 2蛋白，而（+/+）动物的NOS 2蛋白为高，（+/−）为中等。（−/−）小鼠的肾小球和滑膜病理学与（+/−）和（+/+）小鼠相似。然而，（−/−）小鼠和（+/−）小鼠的中等大小肾血管的血管炎明显少于（+/+）小鼠。IgG类风湿因子水平在（−/−）小鼠中显著低于（+/+）小鼠，但抗DNA抗体水平在所有组中相当。我们的研究结果表明，来自NOS 2的NO对MRL-lpr/lpr小鼠的疾病表现有不同的影响，表明疾病机制的异质性。
Nitric oxide (NO) is an important mediator of the inflammatory response. MRL–lpr/lpr mice overexpress inducible nitric oxide synthase (NOS2) and overproduce NO in parallel with the development of an autoimmune syndrome with a variety of inflammatory manifestations. In previous studies, we showed that inhibiting NO production with the nonselective nitric oxide synthase (NOS) inhibitor NG-monomethyl–arginine reduced glomerulonephritis, arthritis, and vasculitis in MRL–lpr/lpr mice. To define further the role of NO and NOS2 in disease in MRL–lpr/lpr mice, mice with targeted disruption of NOS2 were produced by homologous recombination and bred to MRL–lpr/lpr mice to the N4 generation. MRL–lpr/lpr littermates homozygous for disrupted NOS2 (−/−), heterozygous for disrupted NOS2 (+/−), or wildtype (+/+) were derived for this study. Measures of NO production were markedly decreased in the MRL-lpr/lpr (−/−) mice compared with MRL-lpr/lpr (+/+) mice, with intermediate production by the MRL-lpr/lpr (+/−) mice. There was no detectable NOS2 protein by immunoblot analysis of the spleen, liver, kidney, and peritoneal macrophages of the (−/−) animals, whereas that of (+/+) was high and (+/−) intermediate. The (−/−) mice developed glomerular and synovial pathology similar to that of the (+/−) and (+/+) mice. However, (−/−) mice and (+/−) mice had significantly less vasculitis of medium-sized renal vessels than (+/+) mice. IgG rheumatoid factor levels were significantly lower in the (−/−) mice as compared with (+/+) mice, but levels of anti-DNA antibodies were comparable in all groups. Our findings show that NO derived from NOS2 has a variable impact on disease manifestations in MRL-lpr/lpr mice, suggesting heterogeneity in disease mechanisms.
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影响因子：
15.9
作者：
GENARO, AM;HORTELANO, S;BOSCA, L
通讯作者：
BOSCA, L
DOI：
10.1006/clin.1997.4332
发表时间：
1997-04-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
Oates, JC;Ruiz, P;Gilkeson, GS
通讯作者：
Gilkeson, GS
影响因子：
15.3
作者：
Anstey, NM;Weinberg, JB;Granger, DL
通讯作者：
Granger, DL
影响因子：
7
作者：
NATHAN, CF;HIBBS, JB
通讯作者：
HIBBS, JB
DOI：
10.1016/0923-2494(91)90103-p
发表时间：
1991-09-01
期刊：
RESEARCH IN IMMUNOLOGY
影响因子：
--
作者：
HIBBS, JB
通讯作者：
HIBBS, JB