In vivo blockage of nitric oxide with aminoguanidine inhibits immunosuppression induced by an attenuated strain of Salmonella typhimurium, potentiates Salmonella infection, and inhibits macrophage and polymorphonuclear leukocyte influx into the spleen
In vivo blockage of nitric oxide with aminoguanidine inhibits immunosuppression induced by an attenuated strain of Salmonella typhimurium, potentiates Salmonella infection, and inhibits macrophage and polymorphonuclear leukocyte influx into the spleen
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DOI：
10.1128/iai.67.2.891-898.1999
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发表时间：
1999-02-01
影响因子：
3.1
通讯作者：
Eisenstein, TK
中科院分区：
文献类型：
--
作者：
MacFarlane, AS;Schwacha, MG;Eisenstein, TK
我们的实验室先前已经表明，在用鼠伤寒沙门氏菌（Salmonella typhimurium）菌株SL 3235（通过阻断芳香族合成途径而使其无毒）免疫后，小鼠脾细胞在体外对绵羊红细胞产生抗体空斑形成细胞（PFC）应答的能力被严重抑制，证据表明抑制是由一氧化氮（NO）介导的，因为体外加入NG-单甲基-L-精氨酸阻断了抑制。本研究通过在体内给予氨基胍半硫酸盐（AG）来研究阻断NO产生对沙门氏菌诱导的免疫抑制的影响。AG通过饮用水给予C3 HeB/FeJ小鼠（2.5%溶液）培养7天，然后腹膜内接种SL 3235，AG处理抑制了在免疫小鼠中观察到的血浆中硝酸盐和亚硝酸盐水平以及脾脏中亚硝酸盐水平的增加。重要的是，AG处理完全阻断了脾PFC反应的抑制，并显著减弱了免疫小鼠中对伴刀豆球蛋白A的反应的抑制，进一步证明沙门氏菌诱导的免疫抑制是由NO介导的。AG处理还减轻了与SL 3235接种相关的大部分脾肿大，这与中性粒细胞和巨噬细胞流入脾脏的阻断有关，如通过流式细胞术所评估的，AG处理出乎意料地导致注射沙门氏菌高度减毒疫苗菌株SL 3235的小鼠的90%死亡率。与对照组小鼠相比，AG处理小鼠的死亡率增加与接种后第15天无法从脾脏中清除微生物和持续菌血症有关。总的来说，这些体内结果强调了沙门氏菌感染后NO产生的双重生物学后果，NO是宿主防御所必需的，但也具有免疫抑制的潜在不利影响，提出了一个统一的假设来解释这些看似矛盾的影响如何从NO产生。
Our laboratory has previously shown that after immunization with a strain of Salmonella typhimurium, SL3235, made avirulent by a blockage in the pathway of aromatic synthesis, murine splenocytes were profoundly suppressed in their capacity to mount an in vitro antibody plaque-forming cell (PFC) response to sheep erythrocytes, Evidence indicated that suppression was mediated by nitric oxide (NO), since the in vitro addition of NG-monomethyl-L-arginine blocked suppression. The present studies examined the effect of blocking NO production on Salmonella-induced immunosuppression by in vivo administration of aminoguanidine hemisulfate (AG), AG was administered to C3HeB/FeJ mice in their drinking water (2.5% solution) for 7 days prior to intraperitoneal inoculation with SL3235, AG treatment inhibited the increase in nitrate and nitrite levels in plasma and nitrite levels in the spleen seen in immunized mice, Importantly, AG treatment completely blocked suppression of the splenic PFC response and markedly attenuated the suppression of the response to concanavalin A in immunized mice, providing further evidence that Salmonella-induced immunosuppression is mediated by NO. AG treatment also alleviated the majority of the splenomegaly associated with SL3235 inoculation, which correlated with a blockage of influx of neutrophils and macrophages into spleens, as assessed by flow cytometry, AG treatment unexpectedly resulted in 90% mortality in mice injected with the highly attenuated vaccine strain of Salmonella, SL3235. Increased mortality in AG-treated mice correlated with inability to clear organisms from the spleen by day 15 postinoculation and with persistent bacteremia, compared with control mice. Collectively, these in vivo results underscore the dual biological consequences of NO production following Salmonella infection, with NO being necessary for host defense, but also having the potentially adverse effect of immunosuppression, A unifying hypothesis to explain how these seemingly paradoxical effects could both result from NO production is presented.