Abstract
Exposure to indium tin oxide (ITO) nanoparticles (NPs) is strongly correlated with the development of indium lung disease. Preliminary studies have explored mechanisms of ITO NP-induced pulmonary toxicity, but a gap remains in effective methods for risk assessments. To address this issue, we integrated data from population disease databases with traditional toxicology and RNA sequencing to conduct mechanistic studies and establish an adverse outcome pathway (AOP) for ITO NP-induced lung injury. Our findings demonstrate that exposure to ITO NPs induces early pulmonary fibrosis, characterized by a persistent inflammatory response in mice. Mechanistic analysis reveals that lung injury is driven by the activation of the NF-κB signaling pathway mediated by IL-17A in macrophages. In the AOP framework for ITO-induced pulmonary fibrosis, IL-17A serves as a molecular initiating event, initiating the activation of the NF-κB signaling pathway in macrophages. This activation results in the production of inflammatory cytokines (IL-1β and TNF-α) and fibrogenic factors (TGF-β1), ultimately triggering a cellular-level inflammatory response. The sustained inflammation further promotes microvascular leakage, which is a key contributor to the progression of pulmonary fibrosis. The qualitative and quantitative evaluations of supportive inconsistent evidence for MIE and KEs show that the confidence of this AOP is moderate.