Inhibition of the 4-hydroxynonenal-regulated JNK/c-Jun pathway improves bleomycin-induced lung fibrosis

Lipid peroxidation and 4-hydroxynonenal (4-HNE) contribute to oxidative stress-related tissue damage, but their roles in pulmonary fibrosis remain unclear. We examined their involvement in bleomycin-induced pulmonary fibrosis.

Lung fibrosis model mice were used to assess collagen deposition, lipid peroxidation markers, and oxidative stress. Ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine (DFO) were administered to the mice. In vitro, murine lung epithelial (MLE-12) cells were treated with bleomycin, with or without lipid peroxidation inhibitors, and analyzed for oxidative stress and apoptosis. 4-HNE expression in idiopathic pulmonary fibrosis lung tissues was assessed using immunohistochemistry.

Bleomycin increased deposition of collagen and levels of 4-HNE and malondialdehyde levels while decreasing the glutathione/glutathione disulfide ratio. Fer-1 and DFO improved pulmonary function, reduced fibrosis, and restored the glutathione/glutathione disulfide ratio. In vitro, lipid peroxidation inhibition suppressed bleomycin-induced cell death and oxidative stress. Direct 4-HNE treatment induced apoptosis and lipid peroxidation, implicating 4-HNE in epithelial injury. 4-HNE upregulation was linked to increased transforming growth factor-β expression via c-Jun amino-terminal kinase/c-Jun signaling. Fer-1 and DFO mitigated these effects. Human idiopathic pulmonary fibrosis tissues exhibited elevated 4-HNE, correlating with fibrosis severity.

Lipid peroxidation and 4-HNE play key roles in pulmonary fibrosis progression. Their regulation of transforming growth factor-β expression suggests targeting lipid peroxidation as a potential therapeutic strategy.