肠道NDRG2参与PTSD状态下内脏高敏感作用及其机制研究

Role and Mechanism of Intestinal NDRG2 Mediating Visceral Hypersensitivity Following Exposure to PTSD

背景:内脏高敏感是功能性胃肠病(FGIDs)发生的最重要的病理生理学机制。创伤后应激障碍(PTSD)状态下存在广泛的内脏敏感性改变,但在肠道水平敏化的机制尚不清楚。目的:探讨PTSD状态下N-Myc下游调控基因2(NDRG2)在肠道水平参与内脏高敏感的作用。方法:采用单一连续刺激(SPS)方法建立PTSD模型。将SD大鼠分为正常对照组、CTX组、PTSD组、PTSD+CTX组,小鼠分为正常对照组、PTSD组、NDRG2^(-/-)组和NDRG2^(-/-)+PTSD组。采用结直肠扩张法(CRD)和内脏运动反射(VMR)评估大鼠和小鼠的内脏敏感性变化,免疫荧光法评估大鼠肠道NDRG2表达。结果:CRD压力为40、60 mm Hg时,PTSD小鼠的VMR显著高于正常对照小鼠(P=0.033,P=0.021),NDRG2^(-/-)+PTSD组小鼠的VMR显著低于PTSD小鼠(P=0.015,P=0.002)。CRD压力为40、60 mm Hg时,PTSD大鼠的VMR显著高于正常对照大鼠(P=0.003,P<0.001),CTX组VMR显著低于正常对照大鼠(P=0.022,P=0.012),PTSD+CTX组的VMR显著低于PTSD大鼠(P=0.003,P<0.001)。与正常对照大鼠相比,PTSD大鼠结肠NDRG2表达显著增高(P=0.007),CTX大鼠显著降低(P=0.001);与PTSD大鼠相比,PTSD+CTX组大鼠结肠NDRG2表达显著降低(P<0.001)。结论:在PTSD状态下,肠道NDRG2在外周水平参与了内脏高敏感的形成,CTX干预可下调NDRG2表达,从而发挥抗内脏伤害性刺激的作用。

Background:Visceral hypersensitivity is considered as a key pathophysiological mechanism involved in functional gastrointestinal disorders(FGIDs).Visceral nociception and hyperalgesia is existed extensively following exposure to post-traumatic stress disorder(PTSD),however,its molecular mechanism in intestinal tract is unclear.Aims:To explore the potential role of N-Myc downstream-regulated gene 2(NDRG2)in intestinal tract for mediating visceral hypersensitivity following exposure to PTSD.Methods:PTSD model was established by single prolonged stress(SPS).SD rats were divided into normal control group,CTX group,PTSD group and PTSD+CTX group.Mice were divided into normal control group,PTSD group,NDRG2^(-/-)group and NDRG2^(-/-)+PTSD group.Colorectal distention(CRD)and visceromotor reflex(VMR)were used to evaluate visceral sensitivity.Expression of intestinal NDRG2 in rats was detected by immunofluorescence.Results:VMR was significantly increased in the PTSD mice than in normal control mice at CRD pressure of 40 mm Hg and 60 mm Hg(P=0.033,P=0.021),while VMR was significantly decreased in NDRG2^(-/-)+PTSD mice than in PTSD mice(P=0.015,P=0.002).VMR was significantly increased in PTSD rats than in normal control rats at CRD pressure of 40 mm Hg and 60 mm Hg(P=0.003,P<0.001);VMR was significantly decreased in CTX rats than in normal control rats(P=0.022,P=0.012),and VMR was significantly decreased in PTSD+CTX rats than in PTSD rats(P=0.003,P<0.001).Colonic NDRG2 expression was up-regulated in PTSD rats than in normal control rats(P=0.007),and was significantly down-regulated in CTX rats(P=0.001).Colonic NDRG2 expression was down-regulated in PTSD+CTX rats than in PTSD rats(P<0.001).Conclusions:Intestinal NDRG2 at peripheral level is involved in the pathogenesis of visceral hypersensitivity following exposure to PTSD.CTX can attenuate visceral nociceptive hyperalgesia by down-regulating expression of NDRG2.