MAPK inhibitors enhance cell death in pyrogallol-treated human pulmonary fibroblast cells via increasing O₂^•-levels

Pyrogallol (PG) induces apoptosis in lung cancer cells via the overproduction of O₂^•-and affects mitogen-activated protein kinases (MAPKs) in these cells. The aim of the present study was to elucidate the effect of PG and/or MAPK inhibitors on human pulmonary fibroblast (HPF) cell viability in relation to reactive oxygen species (ROS) and glutathione (GSH). Treat-ment with 50 or 100 µM PG inhibited the viability of HPF cells, and induced cell death and the loss of mitochondrial membrane potential (MMP; ΔΨ_m). In particular, treatment with 100 µM PG induced cell death via apoptosis as well as necrosis in HPF cells. PG increased mitochondrial O₂^•-levels and the number of GSH-depleted HPF cells. All the MAPK (mitogen-activated protein kinase kinase, c-Jun N-terminal kinase and p38) inhibitors enhanced the inhibition of cell viability, cell death and MMP (ΔΨ_m) loss in 100 µM PG-treated HPF cells. All the inhibitors increased the O₂^•- levels in 100 µM PG-treated HPF cells, but none of the inhibitors significantly altered the PG-induced GSH depletion. In conclusion, PG treatment induced cell death via apoptosis and necrosis in HPF cells. Treatment with MAPK inhibitors slightly enhanced cell death in PG-treated HPF cells. HPF cell death induced by PG and/or MAPK inhibitors was at least partially associated with changes in O₂^•- levels and GSH content. The present data provided useful information to understand PG-induced normal lung cell death in association with MAPK signaling pathways and ROS levels.