Li Chao, Du Sitong, Lu Yiping, Lu Xiaowei, Liu Fangwei, Chen Ying, Weng Dong, Chen Jie
Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, PR China.
Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China.; Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, PR China.
Theranostics. 2016 Sep 9;6(12):2052-2067. doi: 10.7150/thno.16180. eCollection 2016.
Long term pulmonary exposure to crystalline silica leads to silicosis that manifests progressive interstitial fibrosis, eventually leading to respiratory failure and death. Despite efforts to eliminate silicosis, clinical cases continue to occur in both developing and developed countries. The exact mechanisms of crystalline silica-induced pulmonary fibrosis remain elusive. Herein, we find that 4-1BB is induced in response to crystalline silica injury in lungs and that it is highly expressed during development of experimental silicosis. Therefore, we explore the role of 4-1BB pathway during crystalline silica-induced lung injury and find that a specific inhibitor blocking the pathway could effectively alleviate crystalline silica-induced lung inflammation and subsequent pulmonary fibrosis in vivo. Compared to controls, the treated mice exhibited reduced Th1 and Th17 responses. The concentrations of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF), including tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-17A following crystalline silica challenge were also reduced in inhibitor-treated mice. Although there was no significant alteration in Th2 cytokines of IL-4 and IL-13, another type of pro-fibrogenic cell, regulatory T cell (Treg) was significantly affected. In addition, one of the major participants in fibrogenesis, fibrocyte recruited less due to the blockade. Furthermore, we demonstrated the decreased fibrocyte recruitment was associated with chemokine reductions in lung. Our study discovers the 4-1BB pathway signaling enhances inflammatory response and promotes pulmonary fibrosis induced by crystalline silica. The findings here provide novel insights into the molecular events that control crystalline silica-induced lung inflammation and fibrosis through regulating Th responses and the recruitment of fibrocytes in crystalline silica-exposed lung.
长期肺部暴露于结晶二氧化硅会导致矽肺，表现为进行性间质纤维化，最终导致呼吸衰竭和死亡。尽管努力消除矽肺，但发展中国家和发达国家仍不断出现临床病例。结晶二氧化硅诱导肺纤维化的确切机制仍不清楚。在此，我们发现4-1BB在肺部对结晶二氧化硅损伤的反应中被诱导，并且在实验性矽肺的发展过程中高度表达。因此，我们探讨了4-1BB途径在结晶二氧化硅诱导的肺损伤中的作用，发现阻断该途径的特异性抑制剂可有效减轻体内结晶二氧化硅诱导的肺部炎症和随后的肺纤维化。与对照组相比，经治疗的小鼠Th1和Th17反应降低。在抑制剂治疗的小鼠中，结晶二氧化硅攻击后支气管肺泡灌洗液（BALF）中促炎细胞因子的浓度，包括肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ和白细胞介素（IL）-17A也降低。虽然IL-4和IL-13这两种Th2细胞因子没有显著变化，但另一种促纤维化细胞调节性T细胞（Treg）受到显著影响。此外，纤维化形成的主要参与者之一纤维细胞因阻断而募集减少。此外，我们证明纤维细胞募集减少与肺中趋化因子减少有关。我们的研究发现4-1BB途径信号增强炎症反应并促进结晶二氧化硅诱导的肺纤维化。这里的发现为通过调节Th反应和在暴露于结晶二氧化硅的肺中募集纤维细胞来控制结晶二氧化硅诱导的肺部炎症和纤维化的分子事件提供了新的见解。
