연구결과 I (Inhibition of bleomycin-induced cell death in rat alveolar macrophages and human lung epithelial cells by ambroxol) Mitochondrial permeability transition이 독성, 산화성 세포손상에 관여한다고 제시되고 있음 본 연구는 폐포 대식세포와 폐 상피세포에서 mitochondrial permeability transition를 분석하여, bleomycin (BLM)의 세포독성 효과에 미치는 ambroxo
연구결과 I (Inhibition of bleomycin-induced cell death in rat alveolar macrophages and human lung epithelial cells by ambroxol) Mitochondrial permeability transition이 독성, 산화성 세포손상에 관여한다고 제시되고 있음 본 연구는 폐포 대식세포와 폐 상피세포에서 mitochondrial permeability transition를 분석하여, bleomycin (BLM)의 세포독성 효과에 미치는 ambroxol의 효과를 규명하였음 BLM에 노출된 폐포 대식세포와 폐 상피세포에서 세포사멸과 caspase-3의 활성화가 관찰되었음. Ambroxol $(10-100{\lambda}M)$은 75mU/ml BLM에 의한 핵의 손상, 세포사멸과 caspase-3의 활성화를 억제하였음. Ambroxol 자체는 유의한 세포독성 효과를 나타내지 않았음. BLM은 사림체 막전위의 소실, cytochrome c의 유리, 활성산소의 생성과 GSH의 고갈을 초래하였으며, 이러한 효과는 ambroxol에 의해 억제되었음. Ambroxol은 hydroxyl radical과 nitric oxide에 제거작용을 나타내었으며, 간 조직에서 iron 매개성 malondialdehyde, carbonyl의 형성을 감소시켰음. 이 화합물은 폐 상피세포에서 nitric oxide와 superoxide radical을 생성하는 SIN-1에 의한 세포사멸을 억제하였음. 연구 결과는 ambroxol이 free radical에 대한 제거작용을 통해 사립체 손상을 억제하여, BLM에 의한 세포사멸을 억제한다는 것을 제시하였음 연구결과 II (Differential effect of nitrogen species on changes in mitochondrial membrane permeability due to mitomycin c in lung epithelial cells) 사람 폐 상피세포에서 mitomycin c (MMC)의 세포독성에 미치는 활성질소종 (RNS)의 효과를 사립체 막투과성에 대한 효과로서 분석하였음. 활성질소종은 농도에 따라 MMC의 세포독성에 다른 효과를 나타내었음 MMC에 의한 세포사멸은 caspase-3, 8, 9의 억제제와 항산화제 (N-acetylcysteine, dithiothreitol, ascorbate, rutin)에 의해 억제되었음. 3-Morpholinosydnoninine (SIN-1)은 농도에 따라 MMC에 의한 세포사멸과 GSH의 고갈에 다른 효과를 나타내었으며, $150{\mu}M$에서 최대 억제효과를 나타내었음 Ascorbate, superoxide dismutase와 hemoglobin은 MMC의 세포독성에 미치는 SIN-1의 억제효과를 저해하였음. SIN-1은 MMC에 의한 핵 손상, 사립체 막전위의 소실, cytochrome c의 세포질 축적, caspase-3의 활성화, 활성산소 생성의 증가와 GSH의 고갈을 억제하였음. 또한 SIN-1은 hydrogen peroxide에 의한 세포사멸을 억제하였음. 산화성 물질 또는 RNS 생성물질의 존재하에서 MMC의 세포독성은 MMC와 생성물질 각각의 효과를 합한 것보다 작았음. 연구결과는 사람 폐 상피세포에서 SIN-1이 사립체 막투과성의 변화를 억제하거나 또는 SIN-1 대사물과 MMC의 상호작용에 의해 MMC의 세포독성을 억제한다는 것을 제시하였음
Abstract▼
Result I (Inhibition of bleomycin-induced cell death in rat alveolar macrophages and human lung epithelial cells by ambroxol) The mitochondrial membrane permeability transition is recognized to be involved in toxic and oxidative forms of cell injury. In the present study, we investigated the effe
Result I (Inhibition of bleomycin-induced cell death in rat alveolar macrophages and human lung epithelial cells by ambroxol) The mitochondrial membrane permeability transition is recognized to be involved in toxic and oxidative forms of cell injury. In the present study, we investigated the effect of ambroxol against the cytotoxicity of bleomycin (BLM) by looking at the effect on the mitochondrial membrane permeability in alveolar macrophages and lung epithelial cells. Alveolar macrophages or lung epithelial cells exposed to BLM revealed the loss of cell viability and increase in caspase-3 activity. Ambroxol $(10-100{\mu}M)$ reduced 75mU/mL BLM-induced cell death and activation of caspase-3 in macrophages or epithelial cells. It reduced the condensation and fragmentation of nuclei caused by BLM in macrophages. Ambroxol alone did not significantly cause cell death. Treatment of alveolar macrophages with BLM resulted in the decrease in transmembrane potential in mitochondria, cytosolic accumulation of cytochrome c, increase in formation of reactive oxygen species (ROS) and depletion of GSH. Ambroxol $(10-100{\mu}M)$ inhibited the increase in mitochondrial membrane permeability, ROS formation and decrease in GSH contents due to BLM in macrophages. Ambroxol exerted a scavenging effect on hydroxyl radicals and nitric oxide and reduced the iron-mediated formation of malondialdehyde and carbonyls in liver mitochondria. It prevented cell death due to SIN-1 in lung epithelial cells. The results demonstrate that ambroxol attenuates the BLM-induced viability loss in alveolar macrophages or lung epithelial cells. This effect may be due to inhibition of mitochondrial damage and due to the scavenging action on free radicals. Result II (Differential effect of nitrogen species on changes in mitochondrial membrane permeability due to mitomycin c in lung epithelial cells) The effect of reactive nitrogen species (RNS) on lung epithelial cells against cytotoxicity of mitomycin c (MMC) was assessed by measuring the effect on the mitochondrial membrane permeability. RNS show a differential effect against Cytotoxicity of MMC depending on concentrations. Viability loss in lung epithelial cells exposed to MMC was decreased by inhibitors of caspase-3, 8 and 9 and attenuated by antioxidants (N-acetylcysteine, dithiothreitol, ascorbate and rutin). Addition of 3-morpholinosydnonimine (SIN-1) differentially affected the MMC-induced cell death and GSH depletion depending on concentrations, and at $150 {\mu}M$ SIN-l showed a peak inhibitory effect. Ascorbate, superoxide dismutase and hemoglobin prevented the inhibitory effect of $150 {\mu}M$ SIN-1 on 10 ㎍/ml MMC-induced cell death. SIN-l inhibited the MMC-induced nuclear damage, loss in mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, caspase-3 activation, increase in reactive oxygenspecies (ROS) formation and depletion of GSH in lung epithelial cells. SIN-l attenuaed cell death due to hydrogen peroxide in lung epithelial cells. The cytotoxicity of MMC in the presence of oxidants or RNS producers was much less than the sum of the each effect of MMC and producer. SIN-l may inhibit the MMC-induced viability loss in lung epithelial cells by suppressing the mitochondrial membrane permeability change and by interaction of its products with MMC.
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