Nitric oxide produced in Peyer's patches exhibits antiapoptotic activity contributing to an antimicrobial effect in murine salmonellosis
Nitric oxide produced in Peyer's patches exhibits antiapoptotic activity contributing to an antimicrobial effect in murine salmonellosis
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DOI：
10.1111/j.1348-0421.2008.00030.x
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发表时间：
2008-04-01
影响因子：
2.6
通讯作者：
Akaike, Takaaki
中科院分区：
文献类型：
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作者：
Alam, Mohammad S.;Zaki, Mohammad H.;Akaike, Takaaki
沙门氏菌通常通过口腔-粪便途径感染宿主。我们以前报道过NO在小鼠沙门氏菌病中具有强大的宿主防御功能，不仅通过直接的抗菌作用，而且因为它对感染的宿主细胞具有细胞保护作用。本研究采用口服途径感染感染肠链球菌血清型鼠伤寒菌的inos缺陷小鼠，进一步研究NO在预防PP中沙门氏菌损伤中的细胞保护作用。口服细菌攻击（2 × 10(5) CFU，或bbb100 LD50）在inos缺陷小鼠中比在inos正常小鼠中产生更严重的感染和更高的致死率。在组织化学和免疫组织化学研究中，我们使用了针对肠炎沙门氏菌鼠伤寒杆菌、中性粒细胞、iNOS、硝基酪氨酸和树突状细胞（cd11c阳性）的特异性抗体来检测感染的PP组织。inos缺陷小鼠PP中肠炎鼠伤寒沙门氏菌的定殖量明显高于野生型小鼠。组织化学分析显示PP中有广泛的细胞损伤。然后，我们通过原位TUNEL分析和组织匀浆中caspase-3特异性活性的测量来检测PP组织的凋亡。与野生型小鼠相比，inos缺陷小鼠感染期间观察到tunel阳性细胞数量增加，严重的肉芽肿炎症伴中性粒细胞和巨噬细胞浸润增加。inos缺陷小鼠的树突状细胞数量增加，PP中caspase-3特异性活性显著升高。这些数据证实，NO不仅通过直接抗菌作用发挥其保护功能，还通过防止细胞凋亡，从而在沙门氏菌病期间发挥抗菌防御作用。
Salmonella species normally infect hosts via the oral-fecal route. We previously reported that NO had potent host defense functions in murine salmonellosis, not only via a direct antibacterial effect but also because it was cytoprotective for infected host cells. Here, we used an oral route to infect iNOS-deficient mice infected with S. enterica serovar Typhimurium to further investigate the cytoprotective role of NO in preventing damage caused by Salmonella organisms in PP. Oral bacterial challenge (2 x 10(5) CFU, or > 100 LD50) produced a more severe infection and greater lethality in iNOS-deficient mice than in iNOS-competent mice. We used specific antibodies to S. enterica Typhimurium, neutrophils, iNOS, nitrotyrosine, and dendritic cells (CD11c-positive) in histochemical and immunohistochemical studies to examine infected PP tissues. S. enterica Typhimurium colonization in PP from iNOS-deficient mice was significantly higher than that in wild-type mice. Histochemical assays showed extensive cellular damage in PP. We then examined PP tissues for apoptosis by means of in situ TUNEL analysis and by measuring caspase-3 specific activity in tissue homogenates. Increased numbers of TUNEL-positive cells and severe granulomatous inflammation with increased infiltration of neutrophils and macrophages were observed during infection in iNOS-deficient mice compared with wild-type mice. iNOS-deficient mice had increased numbers of dendritic cells and significantly higher caspase-3-specific activity in PP. These data confirm that NO exerts its protective function not only through direct antibacterial action, but also by preventing apoptosis and thereby contributing to antimicrobial defense during salmonellosis.