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Study on the toxicological mechanism of paraquat-induced pulmonary fibrosis and its tentative therapeutics

百草枯致肺纤维化的毒理机制及其初步治疗研究

基本信息

批准号：
15590571
负责人：
SHIONO Hiroshi
金额：
$ 2.24万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590571/
关键词：
paraquat lung damage oxidative stress ACE inhibitor NO apoptosis 腎障害ドパミン系抗酸化作用

项目摘要

The Paraquat (1,1'-dimethyl-4,4'-bipyridinium, PQ) is a widely used herbicide and is an environmental factor that could be involved in the etiology of Parkinson's disease or at least, exposure to low levels of paraquat for a long time would make dopaminergic neuron vulnerable to oxidative stress and cell death. We have previously shown that paraquat penetrates through the blood-brain barrier and then generates cell death. On the other hand, it is well known that acute poisoning of paraquat induces lung damage, thus the paraquat is a pnemotoxicant possibly as an oxidative-stress inducing substance. However, there is not any effective treatment for paraquat poisoning.In this study, we investigated peripheral acute toxicity, especially to the lung, induced by paraquat (50 mg/kg). The survival rate from paraquat poisoning was significantly higher in mice treated with anti-oxidative agents and/or angiotensin converting enzyme (ACE) inhibitor than control mice which were administered only paraquat. Dopamine transporter inhibitor and dopamine D2/3 agonists, which could be effective to prevent the neuronal damage caused by exposure to low doses of paraquat, did not improve the survival rate but promoted the pulmonary dysfunction caused by 50 mg/kg of paraquat. Since it is known that ACE inhibitor has an anti-oxidative effect, inhibition of oxidative stress might be a key role to reduce the toxicity induced by paraquat in lung. To investigate the oxidative-stress mechanism induced by paraquat in lung tissue, we determined the change of the level of cleaved caspase 3 relevant to apoptotic cell death using the western blot technique.

百草枯(1，1‘-二甲基-4，4’-联吡啶，PQ)是一种广泛使用的除草剂，是一种环境因素，可能与帕金森病的病因有关，或者至少长期暴露于低水平的百草枯会使多巴胺能神经元容易受到氧化应激和细胞死亡的影响。我们之前已经证明，百草枯可以穿透血脑屏障，然后导致细胞死亡。另一方面，百草枯急性中毒会引起肺损伤，因此百草枯是一种可能作为氧化应激诱导物质的化学毒物。然而，目前对百草枯中毒尚无有效的治疗方法。在本研究中，我们研究了百草枯(50 mg/kg)所致的外周急性毒性，尤其是对肺的毒性。接受抗氧化剂和/或血管紧张素转换酶(ACE)抑制剂治疗的小鼠百草枯中毒的存活率显著高于仅服用百草枯的对照小鼠。多巴胺转运体抑制剂和多巴胺D2/3激动剂可有效预防小剂量百草枯引起的神经元损伤，但不能提高存活率，但可促进50 mg/kg百草枯所致的肺功能障碍。已知ACE抑制剂具有抗氧化作用，抑制氧化应激可能是减轻百草枯肺毒性的关键。为探讨百草枯诱导肺组织氧化应激的机制，我们采用免疫印迹技术检测了与细胞凋亡相关的caspase3裂解水平的变化。