Blocking the 4-1BB Pathway Ameliorates Crystalline Silica-induced Lung Inflammation and Fibrosis in Mice.
Blocking the 4-1BB Pathway Ameliorates Crystalline Silica-induced Lung Inflammation and Fibrosis in Mice.
复制标题
阻断 4-1BB 通路可改善结晶二氧化硅诱导的小鼠肺部炎症和纤维化。
作者：
Li C;Du S;Lu Y;Lu X;Liu F;Chen Y;Weng D;Chen J
长期接触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的临床病例仍在继续。结晶性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是对肺内晶状二氧化硅损伤的反应而诱导的，并且在实验性矽肺的发生发展过程中高表达。因此，我们探讨了4-1BB通路在结晶性二氧化硅肺损伤中的作用，发现阻断该通路的特异性抑制剂可以有效地减轻结晶性二氧化硅所致的肺部炎症和随后的体内肺纤维化。与对照组相比，治疗组小鼠的Th1和Th17反应降低。抑制剂组小鼠肺泡灌洗液中肿瘤坏死因子-α、干扰素-γ和白介素17A等促炎细胞因子的浓度也明显降低。尽管Th2细胞因子IL-4和IL-13无明显变化，但另一类促纤维化细胞调节性T细胞(Treg)受到明显影响。此外，作为纤维化形成的主要参与者之一，纤维细胞由于被封锁而招募的人数较少。此外，我们还证明纤维细胞募集的减少与肺内趋化因子的减少有关。我们的研究发现，4-1BB信号通路增强了结晶性二氧化硅诱导的炎症反应，促进了肺纤维化。这些发现为控制结晶性二氧化硅诱导的肺炎症和纤维化的分子事件提供了新的见解，这些分子事件通过调节Th反应和结晶性二氧化硅暴露的肺中纤维细胞的招募来控制。
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.
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影响因子：
3.7
作者：
Liu F;Liu J;Weng D;Chen Y;Song L;He Q;Chen J
通讯作者：
Chen J
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.4049/jimmunol.0803241
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lee SW;Salek-Ardakani S;Mittler RS;Croft M
通讯作者：
Croft M
DOI：
10.1164/rccm.201407-1334oc
发表时间：
2015-02-15
影响因子：
24.7
作者：
de Alba, Carolina Garcia;Buendia-Roldan, Ivette;Selman, Moises
通讯作者：
Selman, Moises
中和白细胞介素 17A 可延缓 C57BL/6 小鼠二氧化硅诱导的肺部炎症和纤维化的进展
影响因子：
3.8
作者：
Chen, Ying;Li, Cuiying;Chen, Jie
通讯作者：
Chen, Jie