Sensitivity of respiratory cell lines to unsaturated carbonyl compounds in cigarette smoke is regulated by intracellular glutathione

Cigarette smoking is a risk factor for various diseases, including chronic obstructive pulmonary disease (COPD). Cell death induced by cigarette smoke is one of the underlying causes of COPD. Unsaturated carbonyl compounds, such as acrolein and methyl vinyl ketone, are major cytotoxic factors in the gas phase of cigarette smoke. To elucidate the molecular mechanisms for induction of cell death by the unsaturated carbonyl compounds in respiratory cells, two lung cancer cell lines, A549 cells and SBC-3 cells, were exposed to the unsaturated carbonyl compounds. A549 cells were resistant to the unsaturated carbonyl compounds, while SBC-3 cells were sensitive to these compounds. Pharmacological analyses revealed that these compounds induce protein kinase C-dependent ferroptosis in SBC-3 cells. Inhibition of glutathione (GSH) synthesis increased the sensitivity of A549 cells to unsaturated carbonyl compounds. GSH level in A549 cells was approximately four times higher than that in SBC-3 cells. Inhibition of SLC7A11, a cystine transporter, in A549 cells increased their sensitivity to unsaturated carbonyl compounds, while overexpression of SLC7A11 in SBC-3 cells decreased their sensitivity to these compounds. These results indicate that the GSH synthetic capacity determines cell sensitivity to unsaturated carbonyl compounds. Accordingly, GSH may be a key factor for the pathogenesis of cigarette smoke-induced COPD.