敗血病腦症之致病機制探討及熱休克前處置之影響

摘要敗血病是造成重症加護病房病人死亡的主要原因。研究報告指出，敗血病會導致腦部功能不良，或引起敗血病腦症，為多器官衰竭過程中最早期之徵候，在敗血病的個案當中，有70%會演變成敗血病腦症，而其死亡率大大的高過於無敗血病腦症的個案。在本實驗室之前的研究發現，給予大白鼠熱休克前處置，可以降低敗血病的死亡率。另外，在缺氧中，或給予藥物誘發癲癇的動物模式下，熱休克前處置皆呈現保護大腦皮質的功能，但對於保護機制仍尚未清楚。在本實驗中，我們利用Spraque-Dawley雄性大白鼠，經由腹腔注射內毒素（劑量為7.5、15和30mg/kg），誘發敗血病的動物模式。實驗動物分為未受處置的控制組、單獨內毒素處理組、和熱休克前處置後再給予內毒素組等三組。隨後以(1)腦波偵測三組大白鼠腦部電氣生理功能的變化，(2)藉由西方點墨法觀察iNOS、Arc及熱休克蛋白質72的表現。結果顯示，熱休克前處置可以降低內毒素引起的腦部生理功能不良，同時減少腦幹部iNOS的表現，及增加腦皮質Arc的表現量。因此，我們認為大白鼠藉由熱休克前處置誘導熱休克蛋白質可藉由，減少腦幹部iNOS蛋白質而增加腦皮質Arc蛋白質的表現，最後降低敗血病導致的腦部病變，這機轉可能是熱休克前處置降低敗血病死亡率的原因之ㄧ。

關鍵字

敗血病腦症；熱休克蛋白 72 ；內毒素

並列摘要

Abstract Systemic sepsis and its consequences are the commonest causes of death in intensive care units. Systemic sepsis frquenttly produces brain dysfunction or sepsis-associated encephalopathy (SAE) which is an early sign and may occur in up to 70% of patients. However, the mechanism is still under investigation. In our previous study, we showed that heat shock (HS) pretreatment reduced mortality in septic rats, and protected the cortical function in hypoxia or drug-induced convulsion. In this study, it was designed to investigate whether the HS plays the protective role in SAE and its possible mechanism was discussed. Male Spraque-Dawley rats were used as the experimental animal and SAE was induced by intraperitoneal injection of Lipopolysaccharide (LPS;7.5,15&30 mg/kg) . Electroencephalography (EEG) was used to evaluate the cortical function. Western blot analysis was used for evaluating the iNOS, Arc and heat shock protein (Hsp) 72. The results showed : (1) The background activity of EEG got slow down 10 minutes after LPS administration in both groups, while those of the heated group was significantly attenuated. (2) Spiky activities were found more abundantly and earlier in non-heated septic rats. (3) LPS (7.5mg/kg)-injected group showed iNOS expression in the brainstem but reduced in the heated LPS-injected group. The amount of Arc, one of immediate early genes, was decreased both in the cortex and hippocampus of LPS (30mg/kg)-injected group. We concluded that LPS injection decreased the cortical electric activity while it could be attenuated by pretreatment of heat shock. Increased synthesis of iNOS in the brainstem and decrease in Arc expression in cortex might participate in the pathogenesis of SAE.