健康与遗传心理学研究室知识库

以前的研究发现情绪应激可明显减少特异性抗卵清蛋白(ovalbumin, OVA)抗体的产生，并激活下丘脑一垂体一肾上腺轴(hypothalamic-pituitary-adrenal,HPA )和交感神经系统(sympathetic nervous system,  SNS)，导致血浆中皮质酮( corticosterone,CORT)和去甲肾上腺素(norepinephrine,NE)水平升高。研究还发现NE的升高与抗体水平呈明显负相关，提示应激诱发的体液免疫抑制可能与SNS有关。为了进一步澄清HPA轴与SNS在应激免疫调节中的作用和参与的受体类型，本文采用药物学方法，以血清抗OVA抗体水平作为体液免疫功能指标，研究应激不同阶段对大鼠体液免疫反应的影响及其调节机制。研究包括如下
两部分:
第一部分研究应激过程中，HPA轴和SNS激活在应激诱发的OVA免疫大鼠特异性抗体反应抑制中的作用机制。研究依次采用6-OHDA化学损毁外周交感神经末梢或糖皮质激素合成抑制剂美替拉酮阻断SNS或HPA轴的作用，采用非选择性p一肾上腺素能受体(adrenergic receptor,ADR)拮抗剂心得安阻断p-ADR作用，以及采用选择性的即一和叩-ADR拮抗剂阿替洛尔和工CI118,551阻断相应受体的作用，结果如下:
    1 6-OHDA外周化学交感切除，逆转了应激的免疫抑制作用，而美替拉酮没有影响，表明应激激活的SNS介导了慢性情绪应激所致大鼠抗OVA抗体水平的降低;
    2非选择性p-ADR拮抗剂心得安可以以剂量依赖的方式逆转情绪应激诱发的体液免疫抑制作用，表明SNS是通过}-ADR介导该作用的;
    3叩-ADR拮抗剂ICI118,551逆转了情绪应激的体液免疫抑制作用，而p1一ADR拮抗剂阿替洛尔没有影响，表明叩-ADR介导应激的免疫调节作用。
    第二部分研究了慢性应激停止后对大鼠体液免疫反应的长期影响及其可能的机制。动物经历了2周或4周情绪应激后，停止应激，经过不同的恢复期((1天或7天)，用牛血清白蛋白(bovine serum albumin, BSA)免疫大鼠。动态观察免疫后14, 21和28天血清抗BSA抗体水平;进一步通过情绪应激前心得安阻断，观察应激过程中SNS激活在应激影响免疫的后效应形成中可能的作用。结果如下:
1 2周应激停止后，经1天恢复期，大鼠抗BSA抗体水平明显降低，应激停止后经7天恢复期，则没有发现抗体水平的改变;而经历4周情绪应激的大鼠无论在应激后1天还是7天，抗体水平都明显低于对照组，表明慢性应激停止后大鼠体液免疫反应仍然受到抑制，抑制持续的时间可能受应激刺激时程的影响;
2情绪应激前心得安阻断p-ADR的作用能逆转慢性应激对大鼠抗体反应的抑制性后效应。    以上结果表明，在慢性情绪应激期间和应激停止后，都发现大鼠体液免疫功能的抑制性
改变。在慢性应激期间，外周SNS在应激所致的体液免疫改变中起着主要作用，且其作用是通过p2-ADR介导的;应激停止后大鼠体液免疫反应仍然受到抑制。应激前心得安阻断p-ADR作用可逆转应激的体液免疫后效应。这提示应激过程中}3 -ADR激活参与慢性应激对大鼠抗体反应抑制性后效应的形成。

    Our  previous  work  demonstrated  that  chronic  stress  activated  both  the hypothalamic-pituitary-adrenal axis (HPA) and the sympathetic nervous system (SNS) (increased the level of corticosterone and norepinephrine in blood，significantly suppressed the level of specific anti-ovalbumine(OVA) IgG antibody production in rats. A negative correlation between antibody and norepinephrine levels was also found,  suggesting  that  sympathetic  nervous  system  may  be  involved  in the stress-induced immunomosuppre}sion. To further clarify the role of HPA axis and SNS and the involvement of receptor types in stress-induced immunosuppression, using  pharmalogical  approaches,  the  present  study  investigated  the  dynamic alterations of humoral immunity in rats during different periods of stress, as well as possible mechanisms. Experiments are divided into two parts.
In the first part, by respectively pretreating rats with the CORT synthesis inhibitor metyrapone and the chemical sympathectomy drug 6-hydroxydopamine to abrogate the role of corticosterone and NE, with the nonselectivep-ADR antagonist propranolol and selective p1-ADR antagonist atenolol and the selective }i2-ADR antagonist ICI118, 551 to block corresponding type/subtype of adrenergic receptors; the mechanisms underlying the decrease of anti-OVA antibody production induced by stress were investigeted. Results are as follows:
    1 Intraperitoneal injection of 6-OHDA but not metyrapone completely blocked the stress suppressive effects on anti-OVA antibody production, suggesting that peripheral SNS postganglionic neurotransmitter NE plays a major role in the stress-induced humoral immunosuppression.
    2 Propranolol reversed the stress-induced humoral immunosuppression in a dose-dependent manner, suggesting that (3-ADR mediated this immunomodulation.
    3 The selective }i2-ADR antagonist ICI118, 551 but not selective [31-ADR antagonist atenolol significantly increased antibody production in stressed rat to normal level.
In the second part, experime-}ts were performed to study the prolonged change of humoral immunoreactivity and its association with basal SNS reactivity (determined by basal NE concentration in plasma) after cessation of chronic stress. Rats were submitted to 2 or 4 weeks chronic stress. All rats were immunized by ip BSA at 1 or 7 days after cessation of stress, and the anti-BSA antibody level was determined at 14,21 and 28 days after immunization. Furthermore, the effects of blockadep-ADR activation  by  propranolol  pretreatment  before  every  stress  episode  on  the immunomodulation post cessation of stress were also studied. Results are as follows:
    1 Immunized at 1 day but not 7 days after cessation of 2-week stress, anti-BSA antibody level in previously stressed rats significantly decreased than that of controls.On the contrary, antibody level of rat experienced 4-week stress  paradigm significantly lower than that of control group at both 1 day and 7 days after cessation of stress. These results showed that humoral immunity of rat was still inhibited after chronic stress schedule.
    2 Propranolol pretreatment restored the decrease of antibody level in previously stressed rats, suggesting thatp-ADR was involved in forming of long-lasting immune changes after chronic stress.
  In summary, these results indicate that there exists inhibitory alteration of humoral immunity in rats during different periods of chronic stress(during and post cessation of chronic stress). SNS plays an important role in the humoral immunosuppression during chronic stress via p2-ADR. After cessation of chronic stress, prolonged alteration of humoral immunosuppression was also observed. Blockade of propranolol reversed this effect, suggestding (3-ADR involved in the forming of stress-induce post-effects on humoral immunity in rats.