Yang Wenyu, Ma Xinrun, Zhu Yong, Meng Xiaoxiao, Tian Rui, Yang Zhengfeng
Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, 650 Xingsongjiang Road, Shanghai 201620, China.
Institute of clinical Immunology, Center for Translational Medicine, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, 650 Xingsongjiang Road, Shanghai 201620, China.
Toxicol Res (Camb). 2021 Jun 17;10(4):733-741. doi: 10.1093/toxres/tfab055. eCollection 2021 Aug.
Paraquat (PQ) and diquat (DQ), two highly efficient herbicides sharing similar chemical backbone, both induce reactive oxygen species and are highly toxic to humans and livestock, however, PQ but not DQ poisoning result in pulmonary fibrosis, the leading cause of high mortality rate in patients suffering PQ toxicity. Understanding the unique mechanism of PQ different from DQ therefore would provide potential strategies to reduce PQ-induced pulmonary fibrosis. Here, we identified that PQ but not DQ continuously upregulates TGF-β expression in alveolar type II (AT II) cells. Importantly, such high expression of TGF-β increases cytosolic calcium levels and further promotes the activation of calcineurin-NFAT axis. TGF-β mainly activates NFATc1 and NFATc2, but not NFATc3 or NFATc4. Administration of the inhibitors targeting cytosolic calcium or calcineurin largely reverses PQ-induced epithelial-mesenchymal transition (EMT), whereas DQ has little effects on activation of NFAT and EMT. Ultimately, PQ poisoned patients exhibit significantly reduced blood calcium levels compared to DQ poisoning, possibly via the large usage of calcium by AT II cells. All in all, we found a vicious cycle that the upregulated TGF-β in PQ-induced EMT further aggravates EMT via promotion of the calcium-calcineurin axis, which could be potential drug targets for treating PQ-induced pulmonary fibrosis.
百草枯（PQ）和敌草快（DQ）是两种具有相似化学结构的高效除草剂，二者均可诱导活性氧的产生，且对人和牲畜都具有高毒性。然而，PQ中毒而非DQ中毒会导致肺纤维化，这是PQ中毒患者高死亡率的主要原因。因此，了解PQ不同于DQ的独特机制将为减少PQ诱导的肺纤维化提供潜在策略。在此，我们发现PQ而非DQ可持续上调II型肺泡上皮细胞（AT II细胞）中转化生长因子-β（TGF-β）的表达。重要的是，TGF-β的这种高表达会增加胞质钙水平，并进一步促进钙调神经磷酸酶-NFAT轴的激活。TGF-β主要激活NFATc1和NFATc2，而非NFATc3或NFATc4。给予靶向胞质钙或钙调神经磷酸酶的抑制剂可在很大程度上逆转PQ诱导的上皮-间质转化（EMT），而DQ对NFAT的激活和EMT几乎没有影响。最终，与DQ中毒相比，PQ中毒患者的血钙水平显著降低，这可能是由于AT II细胞大量消耗钙所致。总而言之，我们发现了一个恶性循环，即PQ诱导的EMT中上调的TGF-β通过促进钙-钙调神经磷酸酶轴进一步加重EMT，这可能是治疗PQ诱导的肺纤维化的潜在药物靶点。
