Role of Cytokines in the Developing Immune System

细胞因子在免疫系统发育中的作用

• 批准号: 7007130
• 负责人: Dori R Germolec
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7007130
• 关键词: age difference; comorbidity; cytokine; developmental immunology; disease /disorder etiology; disease /disorder model; embryo /fetus toxicology; endotoxins; environmental stressor; environmental toxicology; flow cytometry; gene environment interaction; immunocytochemistry; influenza; influenzavirus A; laboratory rat; model design /development; newborn animals; nicotine; nitric oxide; oxidative stress; passive smoking; pathologic process; respiratory infections; sudden infant death syndrome

It has been suggested that SIDS may be a patho-physiological response elicited by combinations of microbial products and/or other environmental factors such as environmental tobacco smoke (ETS) at a time when the developing immune system is more vulnerable to the effects of inflammatory mediators. We have developed an animal model to mimic dual infection, using a non-lethal strain of Influenza A virus and a sub-lethal dose of endotoxin. In this model inoculation with influenza at 10 days of age followed by endotoxin 0.2 mg/kg 2 days post influenza caused mortality with the lowest morbidity. These elements became the defining parameters of the model. Mortality only occurred when specific criteria such as timing between infectious insults and developmental age of the pup were met and age was a key risk factor in the model. We have defined similarities of SIDS pathology in human infants and that seen in this model and examined basic immune factors associated with dual challenge. These studies suggest that the developing immune system can be primed to respond in an exaggerated way to a second immune challenge resulting in unexpected death. To examine the mechanisms underlying this mortality, a series of experiments were conducted to evaluate immune parameters 2-8 hours following endotoxin administration. As the pathologic findings a suggested modulation of systemic immunity rather than lung-specific damage, we evaluated cytokine responses related to systemic shock and oxidative stress. Significant alterations in serum and spleen IFN gamma levels were observed in dually challenged pups, as well as changes in specific immune cell populations in the spleen and lung. Inflammatory cytokine gene expression peaked earlier in dually challenged animals in both the lung and liver. As nitric oxide is an important aspect of the immune response to both bacterial and viral infection, nitric oxide synthase mRNA expression was examined in the target tissues. Increased gene expression was observed in the liver (iNOS, eNOS and nNOS) and the lung (iNOS, eNOS) in dually challenged animals as compared to animal receiving only endotoxin. We also investigated whether intranasal administration of endotoxin, which would more closely mimic potential human exposure, would show similar patterns of immunologic changes. No mortality was observed in animals challenged in this fashion. We are collaborating with Dr. Blood-Siegfried at Duke University to examine the role of environmental tobacco smoke in the development of SIDS using this model. Nicotine exposure appears to prime the immune system in a manner similar to influenza exposure in that nicotine-exposed animals appear to be sensitive to the exposure to bacterial products during a specific developmental window.

已经表明，SIDS可能是由微生物产物和/或其他环境因素（例如环境烟草烟雾（ETS））的组合引起的病理生理反应，此时发育中的免疫系统更容易受到炎症介质的影响。我们已经开发了一种动物模型来模拟双重感染，使用非致死性甲型流感病毒株和亚致死剂量的内毒素。在该模型中，在10日龄接种流感病毒，然后在流感病毒后2天接种内毒素0.2 mg/kg，导致死亡率最低。这些元素成为模型的定义参数。仅当满足特定标准（如感染性损伤之间的时间和幼仔的发育年龄）时才会发生死亡，并且年龄是模型中的关键风险因素。我们已经确定了人类婴儿SIDS病理学的相似性，并在该模型中观察到，并检查了与双重攻击相关的基本免疫因素。这些研究表明，发育中的免疫系统可能会对第二次免疫挑战产生过度反应，导致意外死亡。为了检查导致这种死亡的机制，进行了一系列实验以评估内毒素施用后2-8小时的免疫参数。由于病理结果提示系统性免疫调节而非肺特异性损伤，我们评估了与系统性休克和氧化应激相关的细胞因子反应。在双重激发的幼仔中观察到血清和脾脏IFN γ水平的显著变化，以及脾脏和肺中特异性免疫细胞群的变化。炎症细胞因子基因表达在肺和肝双重攻击的动物达到峰值较早。由于一氧化氮是对细菌和病毒感染的免疫应答的重要方面，因此在靶组织中检测一氧化氮合酶mRNA表达。与仅接受内毒素的动物相比，在双重攻击的动物的肝脏（iNOS、eNOS和nNOS）和肺（iNOS、eNOS）中观察到基因表达增加。我们还研究了内毒素鼻内给药是否会显示类似的免疫学变化模式，内毒素鼻内给药更接近于模拟潜在的人体暴露。在以这种方式激发的动物中未观察到死亡。我们正在与杜克大学的Blood-Siegfried博士合作，利用这一模式研究环境烟草烟雾在小岛屿发展中国家发展中的作用。尼古丁暴露似乎以类似于流感暴露的方式启动免疫系统，因为尼古丁暴露的动物似乎对特定发育窗口期间的细菌产物暴露敏感。

项目成果

Linking environmental agents and autoimmune disease: an agenda for future research.

将环境因素与自身免疫性疾病联系起来：未来研究的议程。

• DOI: 10.1289/ehp.99107s5811
• 发表时间: 1999
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Selgrade,MK;Cooper,GS;Germolec,DR;Heindel,JJ
• 通讯作者: Heindel,JJ

Comparative carcinogenic effects of nickel subsulfide, nickel oxide, or nickel sulfate hexahydrate chronic exposures in the lung.

肺部慢性接触亚硫化镍、氧化镍或六水硫酸镍的比较致癌作用。

• 发表时间: 1995
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Dunnick,JK;Elwell,MR;Radovsky,AE;Benson,JM;Hahn,FF;Nikula,KJ;Barr,EB;Hobbs,CH
• 通讯作者: Hobbs,CH

Introduction to immunology and autoimmunity.

免疫学和自身免疫学简介。

• DOI: 10.1289/ehp.99107s5661
• 发表时间: 1999
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Smith,DA;Germolec,DR
• 通讯作者: Germolec,DR

Epidemiologic associations between occupational and environmental exposures and autoimmune disease: report of a meeting to explore current evidence and identify research needs.

职业和环境暴露与自身免疫性疾病之间的流行病学关联：探讨当前证据并确定研究需求的会议报告。

• DOI: 10.1078/1438-4639-00057
• 发表时间: 2001
• 期刊: International journal of hygiene and environmental health
• 影响因子: 6
• 作者: VanLoveren,H;Vos,JG;Germolec,D;Simeonova,PP;Eijkemanns,G;McMichael,AJ
• 通讯作者: McMichael,AJ

Synergistic effect of influenza a virus on endotoxin-induced mortality in rat pups: a potential model for sudden infant death syndrome.

甲型流感病毒对内毒素诱导的幼鼠死亡率的协同作用：婴儿猝死综合症的潜在模型。

• DOI: 10.1203/00006450-200210000-00005
• 发表时间: 2002
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Blood-Siegfried,Jane;Nyska,Abraham;Lieder,Holly;Joe,Mijeom;Vega,Libia;Patterson,Rachel;Germolec,Dori
• 通讯作者: Germolec,Dori