Sulforaphane attenuates oxidative stress and vascular remodeling in indium lung disease rats via mediating the NF-κB and Nrf2 pathways.

Indium lung disease is characterized by interstitial pneumonia, pulmonary alveolar proteinosis (PAP), pulmonary fibrosis, and lung cancer. However, this is insofar irreversible. The disease is believed to be caused by inhalation of indium and its compounds. We constructed a rat model of indium lung disease to explore the possible role of the NF-κB/Nrf2 pathway in indium‑tin oxide nanoparticle (Nano-ITO)-induced pulmonary injury and to reveal the regulatory mechanism. To integrate computational network toxicology and molecular docking with a rat model to identify core molecular targets and pathways underpinning ITO toxicity, and evaluate whether modulation of the NF-κB/Nrf2 axis by sulforaphane or all-trans retinoic acid mitigates Nano-ITO-induced lung injury. Toxicity prediction, target mining and integration with oxidative stress and vascular remodeling gene sets identified intersection targets that were analyzed by PPI, GO/KEGG/Reactome enrichment and topological analysis to select core nodes. Molecular docking probed interactions between ITO components and proteins in NF-κB/Nrf2 pathways. Next, we evaluated the NF-κB/Nrf2 signaling pathway to elucidate the molecular mechanism of sulforaphane in regulating inflammation, oxidative stress, vascular remodeling, vascular hyperplasia, PAP, cholesterol accumulation, and interstitial fibrosis in indium lung disease induced by Nano-ITO. Findings show that the NF-κB/Nrf2 signaling pathway is involved in Nano-ITO-induced vascular remodeling, cholesterol crystal formation, alveolar protein deposition, collagen hyperplasia, and interstitial fibrosis in rats. Sulforaphane can effectively attenuate Nano-ITO-induced inflammation, oxidative stress and vascular remodeling, as manifested by decreased expression of CD31, α-SMA, Collagen I, SP-A, SP-D, and inflammatory cytokine, via activating Nrf2 and inhibiting the NF-κB signaling pathway.