背景:血栓调节蛋白(TM)具有抗凝和抗炎作用,可提高感染性休克患者的生存率。中暑在许多方面类似于感染性休克。我们测试了TM是否会改善热应激小鼠的认知缺陷和相关致病因素。
方法:将成年雄性小鼠暴露于HS(每天33oC2小时,连续7天)以诱导认知缺陷。重组人可溶性血栓调节蛋白(TM,1mg/kg,i.p.)在第一次HS试验后立即施用,然后每天一次,连续7天。我们做了Y迷宫,新颖的客观识别,和被动回避测试来评估认知功能。脂多糖的血浆水平,高移动性组盒1(HMGB1),凝血参数,并对血浆和组织中炎症和氧化应激标志物的水平进行生化测定。对十二指肠和海马切片进行免疫组织化学染色。测定肠和血脑屏障通透性。
结果:与对照组相比,用TM治疗的HS小鼠的认知缺陷程度较低,加剧了应激反应,肠道屏障破坏,内毒素血症,血脑屏障破坏,和炎症,氧化,和心脏的凝血损伤,十二指肠,和海马组织,和增加血浆HMGB1。除了减少认知缺陷,TM疗法减轻了热应激小鼠的所有上述并发症。
结论:研究结果表明,热应激可导致加重的应激反应,内毒素血症,肠道屏障破坏,血脑屏障破坏,海马炎症,凝血病,和氧化应激,这可能是认知缺陷的致病因素。血栓调节蛋白,一种消炎药,抗氧化剂,和抗凝血剂,抑制热应激诱导的小鼠认知缺陷。
BACKGROUND: Thrombomodulin (TM) exerts anticoagulant and anti-inflammatory effects to improve the survival of patients with septic shock. Heat stroke resembles septic shock in many aspects. We tested whether TM would improve cognitive deficits and related causative factors in heat-stressed (HS) mice.
METHODS: Adult male mice were exposed to HS (33°C for 2 hours daily for 7 consecutive days) to induce cognitive deficits. Recombinant human soluble TM (1 mg/kg, i.p.) was administered immediately after the first HS trial and then once daily for 7 consecutive days. We performed the Y-maze, novel objective recognition, and passive avoidance tests to evaluate cognitive function. Plasma levels of lipopolysaccharide (LPS), high-mobility group box 1 (HMGB1), coagulation parameters, and both plasma and tissue levels of inflammatory and oxidative stress markers were biochemically measured. The duodenum and hippocampus sections were immunohistochemically stained. The intestinal and blood-brain barrier permeability were determined.
RESULTS: Compared with controls, HS mice treated with TM had lesser extents of cognitive deficits, exacerbated stress reactions, gut barrier disruption, endotoxemia, blood-brain barrier disruption, and inflammatory, oxidative, and coagulatory injury to heart, duodenum, and hippocampal tissues, and increased plasma HMGB1. In addition to reducing cognitive deficits, TM therapy alleviated all the abovementioned complications in heat-stressed mice.
CONCLUSIONS: The findings suggest that HS can lead to exacerbated stress reactions, endotoxemia, gut barrier disruption, blood-brain barrier disruption, hippocampal inflammation, coagulopathy, and oxidative stress, which may act as causative factors for cognitive deficits. TM, an anti-inflammatory, antioxidant, and anti-coagulatory agent, inhibited heat stress-induced cognitive deficits in mice.