Abstract：
Silicosis is a global occupational pulmonary disease due to the accumulation of silica dust in the lung. Lacking effective clinical drugs makes the treatment of this disease quite challenging in clinics largely because the pathogenic mechanisms remain obscure. Interleukin 33 (IL33), a pleiotropic cytokine, could promote wound healing and tissue repair via the receptor ST2. However, the mechanisms governing the involvement of IL33 in silicosis progression remain to be further explored. Here, we demonstrated that the IL33 levels in the lung sections were significantly overexpressed after bleomycin and silica treatment. Chromatin immunoprecipitation assay, knockdown, and reverse experiments were performed in lung fibroblasts to prove gene interaction following exogenous IL33 treatment or cocultured with silica-treated lung epithelial cells. Mechanistically, we illustrated that silica-stimulated lung epithelial cells secreted IL33 and further promoted the activation, proliferation, and migration of pulmonary fibroblasts by activating the ERK/AP-1/NPM1 signaling pathway in vitro. And more, treatment with NPM1 siRNA-loaded liposomes markedly protected mice from silica-induced pulmonary fibrosis in vivo. In conclusion, the involvement of NPM1 in the progression of silicosis is regulated by the IL33/ERK/AP-1 signaling axis, which is the potential therapeutic target candidate in developing novel antifibrotic strategies for pulmonary fibrosis.
摘要：
由于肺中二氧化硅粉尘的积累，矽肺是一种全球性的职业性肺病。缺乏有效的临床药物使得这种疾病的治疗在临床上相当具有挑战性,这主要是因为致病机制仍然不清楚。白细胞介素33(IL33),一种多效性细胞因子，可以通过受体ST2促进伤口愈合和组织修复。然而,IL33参与矽肺进展的机制还有待进一步探讨.这里,我们证明,博来霉素(BLM)和二氧化硅处理后,肺切片中的IL33水平显著过表达.染色质免疫沉淀（ChIP）测定，击倒,在外源性IL33处理或与二氧化硅处理的肺上皮细胞共培养后，在肺成纤维细胞中进行反向实验以证明基因相互作用。机械上,我们说明了二氧化硅刺激的肺上皮细胞分泌IL33并进一步促进了激活，扩散,体外激活ERK/AP-1/NPM1信号通路,促进肺成纤维细胞迁移。还有更多,用NPM1siRNA负载的脂质体治疗显著保护小鼠免受二氧化硅诱导的体内肺纤维化。总之,NPM1参与矽肺的进展受IL33/ERK/AP-1信号轴的调节，它是开发新型肺纤维化抗纤维化策略的潜在治疗靶点。
