Hong Jun Sik, Ko Hyun Hee, Han Eun Sook, Lee Chung Soo
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea.
Biochem Pharmacol. 2003 Oct 1;66(7):1297-306. doi: 10.1016/s0006-2952(03)00448-9.
The mitochondrial 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 microM) reduced the 75 mU/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 microM) 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.
线粒体通透性转换被认为与细胞损伤的毒性和氧化形式有关。在本研究中，我们通过观察氨溴索对肺泡巨噬细胞和肺上皮细胞线粒体膜通透性的影响，研究了氨溴索对博来霉素（BLM）细胞毒性的作用。暴露于BLM的肺泡巨噬细胞或肺上皮细胞显示细胞活力丧失和半胱天冬酶-3活性增加。氨溴索（10 - 100微摩尔）减少了75毫单位/毫升BLM诱导的巨噬细胞或上皮细胞的细胞死亡和半胱天冬酶-3的激活。它减少了BLM在巨噬细胞中引起的细胞核凝聚和碎片化。单独使用氨溴索不会显著导致细胞死亡。用BLM处理肺泡巨噬细胞导致线粒体跨膜电位降低、细胞色素c在细胞质中积累、活性氧（ROS）形成增加和谷胱甘肽（GSH）消耗。氨溴索（10 - 100微摩尔）抑制了由于BLM导致的巨噬细胞线粒体膜通透性增加、ROS形成和GSH含量降低。氨溴索对羟自由基和一氧化氮具有清除作用，并减少了铁介导的肝线粒体中丙二醛和羰基的形成。它预防了肺上皮细胞中由于SIN - 1导致的细胞死亡。结果表明，氨溴索减轻了BLM诱导的肺泡巨噬细胞或肺上皮细胞活力丧失。这种作用可能是由于抑制线粒体损伤以及对自由基的清除作用。
