Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University, Changsha, Hunan, PR China; Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, USA.
Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University, Changsha, Hunan, PR China.
Toxicol Lett. 2019 Jun 1;307:1-10. doi: 10.1016/j.toxlet.2019.01.005. Epub 2019 Jan 15.
Paraquat (PQ) poisoning is one of the leading causes of suicide attempts in China signature by acute onset of respiratory distress with massive matrix production resulting in progressive pulmonary fibrosis. There is no specific antidote and mortality remains high without effective treatment available. The cellular mechanisms underlying PQ-induced pulmonary fibrosis remain largely unknown.
To determine the origin of mesenchymal stem cells (MSCs) migrated to the lung after PQ exposure and their roles in PQ-induced pulmonary fibrosis, to further explore the possible mechanisms involved in these processes, and to help finding novel therapies.
We used a combination of lineage tracking techniques to investigate the contributions of several cells of MSCs, marked by Nestin or CXCL12, and traced their co-expression of α-smooth muscle actin (α-SMA), a marker for fibrosis, or their co-location with matrix production, marked by collagen-1 production (Col1-GFP) following PQ exposure. Then, we used a CXCL12flox/flox; Prx1-Cre mice and a pharmacologic agent AMD3100 to selectively deplete chemotactic mechanism of the MSCs, and tested pro-fibrotic pathways, fibrotic processes and survival of mice after PQ exposure.
Our results showed that after paraquat exposure, the residential Nestin + MSCs were quickly expanded and contributed to extracellular matrix production. Moreover, when we used a CXCL12flox/flox; Prx1-Cre mice to selectively deplete chemotactic mechanism of the MSC, we found that PQ exposure in these mice failed to activate pro-fibrotic pathways including TGF-β, Wnt and EGFR signaling. Furthermore, when the chemotactic effect of MSCs via CXCL12 was blocked by a pharmacologic agent, AMD3100, it alleviated the development of the fibrotic process and improved survival rate in mice exposed to PQ.
Collectively, our data suggest paraquat intoxication rapidly activated Nestin + MSCs and that blocking chemotactic effects of MSCs by perivascular CXCL12 inhibition may effectively protect pulmonary injury following paraquat exposure. Our results revealed a novel mechanism for post-PQ lung injury and indicated a novel therapeutic option to attenuate fibrosis induced by paraquat.
百草枯（PQ）中毒是中国导致自杀企图的主要原因之一，其特征为急性呼吸窘迫发作伴大量基质产生，导致进行性肺纤维化。目前尚无特效解毒药，因此死亡率居高不下。PQ 诱导的肺纤维化的细胞机制仍知之甚少。
确定 PQ 暴露后迁移到肺部的间充质干细胞（MSC）的来源及其在 PQ 诱导的肺纤维化中的作用，进一步探讨这些过程中涉及的可能机制，并帮助寻找新的治疗方法。
我们使用谱系追踪技术的组合来研究由巢蛋白或 CXCL12 标记的几个 MSC 细胞的贡献，并追踪它们在 PQ 暴露后的共表达情况，包括α-平滑肌肌动蛋白（α-SMA），纤维化标志物，或它们与胶原-1 产生（Col1-GFP）的共定位，胶原-1 产生是基质产生的标志物。然后，我们使用 CXCL12flox/flox; Prx1-Cre 小鼠和一种药理学药物 AMD3100 选择性耗尽趋化作用机制的 MSC，并测试 PQ 暴露后促纤维化途径、纤维化过程和小鼠的存活率。
我们的结果表明，PQ 暴露后，常驻的巢蛋白阳性 MSC 迅速扩增并参与细胞外基质的产生。此外，当我们使用 CXCL12flox/flox; Prx1-Cre 小鼠选择性耗尽 MSC 的趋化作用机制时，我们发现这些小鼠中的 PQ 暴露未能激活包括 TGF-β、Wnt 和 EGFR 信号在内的促纤维化途径。此外，当通过 CXCL12 阻断 MSC 的趋化作用时，用药理学药物 AMD3100 阻断 MSC 的趋化作用，可减轻 PQ 暴露后纤维化过程的发展并提高小鼠的存活率。
综上所述，我们的数据表明 PQ 中毒可迅速激活巢蛋白阳性 MSC，通过血管周 CXCL12 抑制阻断 MSC 的趋化作用可能有效保护 PQ 暴露后肺损伤。我们的研究结果揭示了 PQ 后肺损伤的新机制，并为减轻 PQ 诱导的纤维化提供了新的治疗选择。
