百草枯的全身毒性及特異性耳毒性作用
發(fā)布時間：2018-07-26 12:50
【摘要】：百草枯是目前全球使用最廣泛的除草劑之一,其對哺乳類生物體的毒性機制主要是在細胞內(nèi)通過反復(fù)氧化還原反應(yīng)而產(chǎn)生大量的過氧化物陰離子并引發(fā)脂質(zhì)過氧化、線粒體損傷、DNA損害、蛋白質(zhì)破壞,最終導(dǎo)致細胞凋亡等級聯(lián)反應(yīng)造成全身多器官的不可逆性損害。百草枯在急性中毒過程往往在肺泡細胞首先表現(xiàn)出特殊的高濃度聚集,這可能是因為百草枯與多胺的化學(xué)結(jié)構(gòu)相似,而肺的Clara細胞和肺泡I型及II型上皮細胞具備較強的多胺轉(zhuǎn)運系統(tǒng),因此百草枯首先積聚在肺的Clara細胞和肺泡I型及II型細胞。百草枯還可穿越血腦屏障并通過多巴胺轉(zhuǎn)運系統(tǒng)在多巴胺神經(jīng)元中積累并首先造成多巴胺神經(jīng)元的破壞,因此,百草枯慢性中毒可能與帕金森病的發(fā)病機制也具有一定的關(guān)系。各種耳毒性藥物和強噪聲以及重金屬和老年性耳聾引起的內(nèi)耳損傷都與氧自由基的損害作用密切相關(guān),百草枯對細胞的氧化損傷作用使之成為研究內(nèi)耳自由基損害和抗氧化劑保護效應(yīng)的理想研究模型之一。百草枯引起的實驗動物聽覺障礙表現(xiàn)出高頻聽力首先受損的特點,百草枯引起的耳蝸毛細胞損害則首先發(fā)生在耳蝸底回對應(yīng)高頻聽覺反應(yīng)的區(qū)域。在百草枯引起的受損耳蝸細胞內(nèi),過氧化物陰離子首先在細胞質(zhì)中的表達增強,隨后凝聚到細胞核內(nèi),說明耳蝸細胞的損害確實是因為細胞內(nèi)首先發(fā)生的氧化應(yīng)激所引起,而這種自由基損害最終啟動了細胞的自毀裝置而導(dǎo)致了細胞的凋亡。我們在最近的實驗研究中發(fā)現(xiàn),百草枯對耳蝸細胞的損害首先是發(fā)生在耳蝸毛細胞底部和周圍的支持細胞,由于這些支持細胞的破壞造成耳蝸Corti器的支持結(jié)構(gòu)塌陷,從而使耳蝸毛細胞因失去周圍細胞的連接和支持而發(fā)生排列散亂和位置漂移,這種因失去細胞之間的聯(lián)系而發(fā)生的毛細胞"失巢凋亡"可能也是造成毛細胞破壞的重要機制之一。因此,百草枯引發(fā)的毛細胞凋亡不僅與細胞內(nèi)發(fā)生的各種自由基損害有關(guān),而且因喪失與周圍支持細胞相聯(lián)系的外基質(zhì)而引發(fā)"失巢凋亡",顯然這是一個值得思考的更重要的可能性損害機制。
[Abstract]:Paraquat is one of the most widely used herbicides in the world. The toxic mechanism of paraquat on mammalian organisms is to produce a large number of peroxide anions and induce lipid peroxidation through repeated redox reactions in cells. Mitochondria damage DNA damage, protein damage, and eventually lead to apoptosis grade reaction, resulting in irreversible damage to multiple organs. Paraquat tends to exhibit a special high concentration of aggregation in alveolar cells during acute poisoning, which may be due to the chemical structure of paraquat and polyamines. However, Clara cells and type I and type II epithelial cells of the lung have strong polyamine transport system, so paraquat first accumulates in the Clara cells and type I and type II cells of the lung. Paraquat can also cross the blood-brain barrier and accumulate in the dopamine neurons through the dopamine transporter system. Therefore, the chronic paraquat poisoning may be related to the pathogenesis of Parkinson's disease. All kinds of ototoxic drugs and strong noise, as well as heavy metals and deafness caused by the inner ear damage are closely related to the damage of oxygen free radicals, The oxidative damage of paraquat to cells makes it an ideal model to study the damage of inner ear free radicals and the protective effect of antioxidants. Paraquat induced hearing impairment in laboratory animals showed the characteristics of high frequency hearing loss first. Paraquat induced cochlear hair cell damage first occurred in the region of cochlear basal gyrus corresponding to high frequency auditory response. In the damaged cochlear cells induced by paraquat, the expression of peroxide anion was increased first in the cytoplasm and then condensed into the nucleus, indicating that the damage of the cochlear cells was indeed caused by the oxidative stress that occurred first in the cells. This free-radical damage eventually activates cell self-destruction and leads to cell apoptosis. In our recent experimental study, we found that paraquat damage to cochlear cells was primarily caused by supporting cells at and around the bottom of the cochlear hair cells, which caused the collapse of the supporting structure of the Corti organ in the cochlea. Thus, the hair cells of the cochlea lose the connection and support of the surrounding cells and cause the arrangement and position drift of the hair cells in the cochlea. The loss of the relationship between hair cells may also be one of the important mechanisms of hair cell destruction. Therefore, the apoptosis of hair cells induced by paraquat is not only related to the damage of free radicals occurring in the cells, Moreover, the loss of the extracellular matrix associated with peripheral Sertoli cells leads to "loss of nesting and apoptosis", which is obviously a more important possible damage mechanism to be considered.
【作者單位】： 中南大學(xué)附屬湘雅醫(yī)院耳鼻咽喉頭頸外科;Center
【基金】：“973”國家重大科學(xué)研究計劃項目(2014CB943003) 國家自然科學(xué)基金面上項目(81170912)~~
【分類號】：R595.4;R764
本文編號：2146068
[Abstract]:Paraquat is one of the most widely used herbicides in the world. The toxic mechanism of paraquat on mammalian organisms is to produce a large number of peroxide anions and induce lipid peroxidation through repeated redox reactions in cells. Mitochondria damage DNA damage, protein damage, and eventually lead to apoptosis grade reaction, resulting in irreversible damage to multiple organs. Paraquat tends to exhibit a special high concentration of aggregation in alveolar cells during acute poisoning, which may be due to the chemical structure of paraquat and polyamines. However, Clara cells and type I and type II epithelial cells of the lung have strong polyamine transport system, so paraquat first accumulates in the Clara cells and type I and type II cells of the lung. Paraquat can also cross the blood-brain barrier and accumulate in the dopamine neurons through the dopamine transporter system. Therefore, the chronic paraquat poisoning may be related to the pathogenesis of Parkinson's disease. All kinds of ototoxic drugs and strong noise, as well as heavy metals and deafness caused by the inner ear damage are closely related to the damage of oxygen free radicals, The oxidative damage of paraquat to cells makes it an ideal model to study the damage of inner ear free radicals and the protective effect of antioxidants. Paraquat induced hearing impairment in laboratory animals showed the characteristics of high frequency hearing loss first. Paraquat induced cochlear hair cell damage first occurred in the region of cochlear basal gyrus corresponding to high frequency auditory response. In the damaged cochlear cells induced by paraquat, the expression of peroxide anion was increased first in the cytoplasm and then condensed into the nucleus, indicating that the damage of the cochlear cells was indeed caused by the oxidative stress that occurred first in the cells. This free-radical damage eventually activates cell self-destruction and leads to cell apoptosis. In our recent experimental study, we found that paraquat damage to cochlear cells was primarily caused by supporting cells at and around the bottom of the cochlear hair cells, which caused the collapse of the supporting structure of the Corti organ in the cochlea. Thus, the hair cells of the cochlea lose the connection and support of the surrounding cells and cause the arrangement and position drift of the hair cells in the cochlea. The loss of the relationship between hair cells may also be one of the important mechanisms of hair cell destruction. Therefore, the apoptosis of hair cells induced by paraquat is not only related to the damage of free radicals occurring in the cells, Moreover, the loss of the extracellular matrix associated with peripheral Sertoli cells leads to "loss of nesting and apoptosis", which is obviously a more important possible damage mechanism to be considered.
【作者單位】： 中南大學(xué)附屬湘雅醫(yī)院耳鼻咽喉頭頸外科;Center
【基金】：“973”國家重大科學(xué)研究計劃項目(2014CB943003) 國家自然科學(xué)基金面上項目(81170912)~~
【分類號】：R595.4;R764
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