P. aeruginosa Induced Lipid Peroxidation Causes Ferroptotic Cell Death in Airways

Oxidative stress and infections by Pseudomonas aeruginosa (P. aeruginosa) are prominent in lungs of patients suffering from cystic fibrosis (CF).

The present study examines effects of P. aeruginosa on lipid peroxidation in human and mouse lungs, and cell death induced by P. aeruginosa in human airway epithelial cells. The role of the Ca²⁺ activated Cl^- channel TMEM16A, the phospholipid scramblase TMEM16F, and the CFTR Cl^- channel for ferroptotic cell death is examined.

Lipid peroxidation was detected in human CF lungs, which correlated with bacterial infection. In vivo inoculation with P. aeruginosa or Staphylococcus aureus (S. aureus) induced lipid peroxidation in lungs of mice lacking expression of CFTR, and in lungs of wild type animals. Incubation of CFBE human airway epithelial cells with P. aeruginosa induced an increase in reactive oxygen species (ROS), causing lipid peroxidation and cell death independent of expression of wt-CFTR or F508del-CFTR. Knockdown of TMEM16A attenuated P. aeruginosa induced cell death. Antioxidants such as coenzyme Q10 and idebenone as well as the inhibitor of ferroptosis, ferrostatin-1, inhibited P. aeruginosa-induced cell death. CFBE cells expressing wtCFTR, but not F508del-CFTR, activated a basal Cl^- conductance upon exposure to P. aeruginosa, which was caused by an increase in intracellular basal Ca²⁺ concentrations and activation of Ca²⁺-dependent adenylate cyclase.

The data suggest an intrinsic pro-inflammatory phenotype in CF epithelial cells, while ferroptosis is observed in both non-CF and CF epithelial cells upon infection with P. aeruginosa. CF cells fail to activate fluid secretion in response to infection with P. aeruginosa. The use of antioxidants and inhibitors of ferroptosis is proposed as a treatment of pneumonia caused by infection with P. aeruginosa.