Glutathione deficiency & immune dysfunction during aging

描述：(申请人提供)肺泡巨噬细胞(AM)的功能， 是肺部抗菌和抗病毒防御的一个非常重要的组成部分， 随着年龄的增长而减少。伴随而来的是传染性疾病的发病率和严重性 肺部疾病随着年龄的增长而增加，对急性呼吸道疾病的敏感性也随着年龄的增长而增加。 03和NO2这两种重要环境污染物的毒性 AM功能。这种年龄相关性下降背后的机制是 AM的免疫功能和对03和NO2毒性的敏感性增加， 然而，目前还不清楚。谷胱甘肽(GSH)是一种重要的抗氧化剂，它在 在维持免疫系统的最佳功能方面发挥关键作用。谷胱甘肽 随着年龄的增长，GSH浓度会下降，而补充GSH则会恢复或改善 免疫功能，特别是在老年人中，表明有潜在的 谷胱甘肽缺乏与年龄相关性免疫功能障碍的关系 系统。我们之前的研究进一步表明，表达减少的 新生物中的限速酶--谷氨酰半胱氨酸合成酶 GSH的合成，至少是年龄相关性的下降的部分原因 大鼠组织中GSH含量。然而，AM的GSH含量是否随着年龄的增长而降低？ 如果是这样，潜在的机制是什么？最重要的是，它减少了 GSH含量与AM年龄相关性功能障碍及升高的关系 老年人对传染性肺部疾病以及03和NO2的易感性 毒性？所有这些问题都有待回答。这样做的具体目的是 项目有1)确定小鼠AM中的GSH含量是否随着 年龄和潜在的潜在机制。2)检验假设 GCS基因表达减少是年龄相关性疾病下降的原因 肺泡巨噬细胞GSH含量与功能障碍及其敏感性的关系 老年人易患传染性肺部疾病。四环素诱导的巨噬细胞 特异性GCS正义和反义基因转基因小鼠模型将用于 检验这一假设。AM功能与小鼠对肺炎球菌的抵抗力 将确定感染是否会增加GCS基因的表达和 GSH含量能恢复老年小鼠AM的功能，并降低 他们的肺部感染。3)确定增加的敏感度是否 老年人对03或NO2引起的急性毒性是由于GSH降低所致 AM的含量和功能障碍这个项目的长期目标是 揭示AM功能障碍和易感性增加的机制 对老年人感染性肺部疾病和臭氧/亚硝酸盐毒性的影响 为治疗这些疾病提供治疗策略。

DESCRIPTION: (provided by applicant) The function of alveolar macrophages (AM), a very important component of lung antibacterial and antiviral defense, decreases with age. Concomitantly, the incidence and the severity of infectious lung diseases increase with age and so does the sensitivity to the acute toxicity of 03 and NO2, two important environmental pollutants, which suppress AM function. The mechanisms underlying such age-associated decline in the immune function of AM and increase in sensitivity to 03 and NO2 toxicity, however, are not clear. Glutathione (GSH), an important antioxidant, plays a critical role in maintaining the optimal function of the immune system. GSH concentration decreases with age while GSH supplementation restores or improves the immune function, especially in the elderly, suggesting a potential involvement of GSH deficiency in age-associated dysfunction of the immune system. Our previous studies further suggest that decreased expression of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in de novo GSH synthesis, is at least partially responsible for age-associated decline in GSH content in rat tissues. However, does GSH content decrease with age in AM? If it does, what is the underlying mechanism? Most importantly, is decreased GSH content responsible for age-associated dysfunction of AM and increased susceptibility of the elderly to infectious lung diseases as well as 03 and NO2 toxicity? All these questions remain to be answered. The specific aims of this project are 1) To determine whether the GSH content in murine AM decreases with age and the potential underlying mechanism. 2) To test the hypothesis that decreased GCS gene expression is responsible for the age-associated decline in GSH content and dysfunction of AM as well as increased sensitivity of the elderly to infectious lung diseases. Tetracycline inducible, macrophage specific GCS sense and antisense gene transgenic mouse models will be used to test this hypothesis. AM function as well as resistance of mice to pneumococci infection will be determined to see whether increasing GCS gene expression and GSH content will restore the function of AM from old mice as well as reduce their lung infection. 3) To determine whether increased sensitivity of the elderly to the acute toxicity caused by 03 or NO2 is due to a decreased GSH content and dysfunction of AM. The long-term objective of this project is to uncover the mechanism underlying dysfunction of AM and increased susceptibility to infectious lung diseases and O3/NO2 toxicity observed in the elderly and to provide therapeutic strategies for treatment of these diseases.