Inhibition of bleomycin-induced cell death in rat alveolar macrophages and human lung epithelial cells by ambroxol.
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.
D000551:Ambroxol / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001761:Bleomycin / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D005100:Expectorants / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species
D003574:Cytochrome c Group; D005100:Expectorants; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D001761:Bleomycin; D000551:Ambroxol; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione