Li Guo, Yuzhen Li, Yi Chen, Xiaoxiang Chen, Wei Zhou, Changqing Zhu, Shuang Ye
Department of Rheumatology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
Department of Emergency Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
Biomed Res Int. 2015;2015:386952. doi: 10.1155/2015/386952. Epub 2015 Feb 11.
Paraquat (PQ) poisoning is a lethal toxicological challenge that served as a disease model of acute lung injury and pulmonary fibrosis, but the mechanism is undetermined and no effective treatment has been discovered.
We demonstrated that PQ injures mitochondria and leads to mtDNA release. The mtDNA mediated PBMC recruitment and stimulated the alveolar epithelial cell production of TGF-β1 in vitro. The levels of mtDNA in circulation and bronchial alveolar lavage fluid (BALF) were elevated in a mouse of PQ-induced lung injury. DNaseI could protect PQ-induced lung injury and significantly improved survival. Acute lung injury markers, such as TNFα, IL-1β, and IL-6, and marker of fibrosis, collagen I, were downregulated in parallel with the elimination of mtDNA by DNaseI. These data indicate a possible mechanism for PQ-induced, mtDNA-mediated lung injury, which may be shared by other causes of lung injury, as suggested by the same protective effect of DNaseI in bleomycin-induced lung injury model. Interestingly, increased mtDNA in the BALF of patients with amyopathic dermatomyositis-interstitial lung disease can be appreciated.
DNaseI targeting mtDNA may be a promising approach for the treatment of PQ-induced acute lung injury and pulmonary fibrosis that merits fast tracking through clinical trials.
百草枯（PQ）中毒是一项致命的毒理学挑战，可作为急性肺损伤和肺纤维化的疾病模型，但机制尚未明确，且未发现有效治疗方法。
我们证明PQ会损伤线粒体并导致线粒体DNA（mtDNA）释放。mtDNA在体外介导外周血单个核细胞（PBMC）募集并刺激肺泡上皮细胞产生转化生长因子-β1（TGF-β1）。在PQ诱导的肺损伤小鼠中，循环血液和支气管肺泡灌洗液（BALF）中的mtDNA水平升高。脱氧核糖核酸酶I（DNaseI）可保护PQ诱导的肺损伤并显著提高生存率。急性肺损伤标志物，如肿瘤坏死因子α（TNFα）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6），以及纤维化标志物I型胶原，随着DNaseI清除mtDNA而平行下调。这些数据表明了PQ诱导的、mtDNA介导的肺损伤的一种可能机制，正如DNaseI在博来霉素诱导的肺损伤模型中的相同保护作用所表明的，其他肺损伤原因可能也存在这种机制。有趣的是，无肌病性皮肌炎-间质性肺疾病患者的BALF中mtDNA增加。
靶向mtDNA的DNaseI可能是治疗PQ诱导的急性肺损伤和肺纤维化的一种有前景的方法，值得通过临床试验快速跟进。
