Abstract

Hypoxia occurs during silicosis progression; however, the mechanisms by which silica induces hypoxia and its precise role in the pathogenesis remain poorly understood. In this study, 50 male rats were assigned to five groups: a control group, a model group, and three intervention groups. The rats in the model and intervention groups were intratracheally administered a silica suspension only once, whereas the control rats were intratracheally administered phosphate buffer solution (PBS). Then the rats in intervention groups received daily intravenous injections of N -acetylcysteine (NAC) (at doses of 20, 40, and 80 mg/kg, respectively) while the rats in control and model groups received PBS injections. After 60 days, the lung samples were harvested for histopathologic evaluation, and the hypoxia-related proteins (nuclear factor-κB p65 [NF-κB p65], hypoxia-inducible factor-1α [HIF-1α], and vascular endothelial growth factor A [VEGFA]), lactate-metabolism markers (glucose transporter type 1 [GLUT1] and lactate dehydrogenase A [LDHA]), and pulmonary-injury indicators (interleukin-1β [IL-1β] and transforming growth factor-β1 [TGF-β1]) were quantified using Western blot. The results showed that compared with the control group, the lung of the model group exhibited obvious damage and collagen deposition, accompanied by upregulation of the aforementioned cytokines. When NAC was employed to inhibit silica-induced ROS, all of the above phenomena were reversed in a dose-dependent manner. These findings indicated that silica induced pulmonary hypoxia via the ROS/NF-κB p65 pathway, which subsequently triggered inflammation and fibrosis through lactic acid fermentation, ultimately leading to silicosis.