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

为了研究星形胶质细胞对神经元的细胞旁保护机制，在缺血大鼠脑中进行了免疫组织化学分析，该分析与死亡的TUNEL阳性神经元周围星形胶质细胞中血红素氧合e1 （HO-1）的表达共定位。作为体外缺血模式，培养的星形胶质细胞暴露于常压缺氧（pO2 ~ 10 torr），可触发33 kDa应激蛋白HO-1的表达增加约120倍。缺氧4小时内观察到HO-1信息的诱导，12小时达到峰值，并伴有HO-1信息转录的加速。与HO-1的诱导一致，血小板生物测定显示再氧化星形胶质细胞产生一氧化碳。培养基中CO的存在通过降低调节凋亡细胞死亡的关键酶CPP32的活性，减缓了培养小脑神经元缺氧介导的凋亡型细胞死亡。这种对细胞凋亡的保护可能是由co介导的细胞内cGMP水平的增加介导的，在缺氧神经元培养物中添加cGMP类似物可抑制CPP32活性并促进神经元存活。这些数据描述了一个潜在的重要的细胞旁通路，星形胶质细胞可以通过它来拯救缺血性死亡的邻近神经元。

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.