PDF(Pubmed)
Abstract：
Fever plays an indispensable role in host defense processes and is used as a rapid index of infection severity. Unfortunately, there are also substantial individual differences in fever reactions with biological sex, immunological history, and other demographic variables contributing to adverse outcomes of infection. The present series of studies were designed to test the hypothesis that a history of adolescent alcohol misuse may be a latent experiential variable that determines fever severity using polyinosinic:polycytidylic acid (poly I:C), a synthetic form of double-stranded RNA that mimics a viral challenge. Adult male and female Sprague Dawley rats were injected with 0 (saline) or 4 mg/kg poly I:C to first establish sex differences in fever sensitivity in Experiment 1 using implanted radiotelemetry devices for remote tracking. In Experiments 2 and 3, adolescent males and females were exposed to either water or ethanol (0 or 4 g/kg intragastrically, 3 days on, 2 days off, ∼P30-P50, 4 cycles/12 exposures total). After a period of abstinence, adult rats (∼P80-96) were then challenged with saline or poly I:C, and fever induction and maintenance were examined across a prolonged time course of 8 h using implanted probes. In Experiments 4 and 5, adult male and female subjects with a prior history of adolescent water or adolescent intermittent ethanol (AIE) were given saline or poly I:C, with tissue collected for protein and gene expression analysis at 5 h post-injection. Initial sex differences in fever sensitivity were minimal in response to the 4 mg/kg dose of poly I:C in ethanol-naïve rats. AIE exposed males injected with poly I:C showed a sensitized fever response as well as enhanced TLR3, IκBα, and IL-1β expression in the nucleus of the solitary tract. Other brain regions related to thermoregulation and peripheral organs such as spleen, liver, and blood showed generalized immune responses to poly I:C, with no differences evident between AIE and water-exposed males. In contrast, AIE did not affect responsiveness to poly I:C in females. Thus, the present findings suggest that adolescent binge drinking may produce sex-specific and long-lasting effects on fever reactivity to viral infection, with preliminary evidence suggesting that these effects may be due to centrally-mediated changes in fever regulation rather than peripheral immunological mechanisms.
摘要：
发热在宿主防御过程中起着不可或缺的作用，并被用作感染严重程度的快速指标。不幸的是,发烧反应与生物性别也有很大的个体差异，免疫学史,和其他导致感染不良结果的人口统计学变量。本系列研究旨在检验以下假设：青少年酒精滥用史可能是潜在的经验变量，可确定使用聚肌苷酸：聚胞嘧啶酸（聚I：C）的发烧严重程度，一种模拟病毒攻击的双链RNA的合成形式。成年雄性和雌性SpragueDawley大鼠注射0（盐水）或4mg/kgpolyI：C，首先在实验1中使用植入的放射性遥测设备进行远程跟踪，以建立发烧敏感性的性别差异。在实验2和3中，青春期的男性和女性暴露于水或乙醇（胃内暴露于0或4g/kg，3天之后,休息2天,P30-P50，共4个周期/12个曝光）。经过一段时间的禁欲，然后用盐水或polyI:C攻击成年大鼠(~P80-96)，使用植入的探针在8小时的延长时间内检查了发热的诱导和维持。在实验4和5中，有青少年饮水或青少年间歇性乙醇（AIE）病史的成年男性和女性受试者被给予生理盐水或polyI：C，在注射后5小时收集组织进行蛋白质和基因表达分析。在未处理乙醇的大鼠中,响应于4mg/kg剂量的聚I:C,发热敏感性的初始性别差异最小。注射polyI：C的AIE暴露雄性显示出致敏的发热反应以及增强的TLR3，IκBα，和IL-1β在孤束核中的表达。与体温调节相关的其他大脑区域和外周器官，如脾脏，肝脏,血液对polyI:C表现出广泛的免疫反应，AIE和水暴露的雄性之间没有明显差异。相比之下,AIE不影响女性对polyI：C的反应性。因此，目前的研究结果表明，青少年暴饮暴食可能会对病毒感染的发热反应产生性别特异性和持久的影响，初步证据表明，这些作用可能是由于中央介导的发热调节变化，而不是外周免疫机制。
