Fluoride-induced apoptosis in epithelial lung cells involves activation ofMAP kinases p38 and possibly JNK

Exposure to fluorides can induce inflammatory reactions, cell cycle arrest, and apoptosis in different experimental systems, Fluorides are known G-pro tein activators, but less is known about fluoride effects downstream of G-p rotein activation. The aim of this study was to elucidate whether the induc tion of apoptosis by fluorides and inhibition of proliferation is mediated by MAP kinases in primary rat lung, alveolar type 2 cells and the human epi thelial lung cell line A549. Sodium fluoride (NaF) induced apoptosis in bot h cell types but at different concentrations, with the primary cells being more sensitive to NaF, Proliferation of the type 2 cells and A549 cells was inhibited in the presence of NaF, NaF induced a prolonged activation of MA P kinase ERK, NaF also activated p38 and JNK in A549 cells for several hour s (maximally 6-fold and 3-fold increase, respectively), Inhibition of ERK w ith the MEK1,2 inhibitor PD98059 increased apoptosis I-fold, whereas the in hibitor of p38, SB202190. decreased the level of apoptotic cells by approxi mately 40%. SB202190 also inhibited apoptosis by almost 40% when ERK activi ty was reduced in the presence of PD98059. Neither PD98059 nor SB202190 did affect the NaF-induced inhibition of proliferation, These observations ind icate that activation of MAP kinases p38 and possibly JNK are involved in N aF-induced apoptosis of epithelial lung cells, whereas ERK activation seems to counteract apoptosis in epithelial lung cells. In contrast, activation of ERR and p38 are not involved in NaF-induced inhibition of cell prolifera tion.