Hypoxia-Mediated induction of heme oxygenase type I and carbon monoxide release from astrocytes protects nearby cerebellar neurons from hypoxia-mediated apoptosis.

为探讨星形胶质细胞对神经元的细胞旁保护机制，采用免疫组织化学方法观察了缺血大鼠脑内血红素氧合酶1(HO-1)在死亡、TUNEL阳性神经元周围星形胶质细胞中的表达。作为一种体外脑缺血模型，培养的星形胶质细胞暴露在常压低氧(pO2~10torr)中，引起33 kDa应激蛋白HO-1的表达增加约120倍。H0-1信息的诱导在缺氧4小时内出现，12小时达到高峰，伴随着HO-1信息的加速转录。与HO-1的诱导一致，血小板生物测定显示，复氧后的星形胶质细胞产生一氧化碳。培养液中CO的存在通过降低调节细胞死亡的关键酶CPP32的活性来减缓培养的小脑神经元缺氧诱导的细胞死亡。这种对细胞凋亡的保护作用可能是通过CO介导的细胞内cGMP水平的增加而实现的，在低氧神经元培养中加入cGMP类似物可抑制CPP32的活性并促进神经元的存活。这些数据描述了一条潜在的重要的细胞旁途径，星形胶质细胞可能通过该途径将新生神经元从缺血性死亡中拯救出来。

To study a putative paracellular protective mechanism of astrosytes for neurons, immunohistochemical analysis was performed in ischemic rat brain, which colocalized with the expression of heme oxygase1 (HO-1) in astrocytes surrounding dying, TUNEL positive neurons. As an in vitro paradigm for ischemia, cultured astrocytes were exposed to normobaric hypoxia(pO2〜10 torr), which triggered〜120-fold increase in the expression of a 33 kDa stress protein, identiried as HO-1. Induction of H0-1 message was observed within 4 hrs of hypoxia and peaked at 12 hours, accompanied by an accelerated transcription of HO-1 message. Consistent with the induction of HO-1 a platelet bioassay revealed production of carbon monoxide by reoxygenated astrocytes. The presence of CO in the medium decelerated the hypoxiamediated apoptotic type of cell death in cultreud cerebellar neurons via lowering the activity of CPP32, a key enzyme regulating apoptotic cell death. This protection against apoptosis was likely mediated by CO-mediated increases in intracellular cGMP levels, and addition of cGMP analogue to hypoxic neuronal cultures suppressed CPP32 activity and promoted neuronal survival. These data describe a potentially important paracellular pathway through which astrocytes may rescue neaby neurons from ischemic death.