Alterations in the proteome of the respiratory tract in response to single and multiple exposures to naphthalene.
Alterations in the proteome of the respiratory tract in response to single and multiple exposures to naphthalene.
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DOI：
10.1002/pmic.201400445
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发表时间：
2015-08
期刊：
影响因子：
3.4
通讯作者：
Van Winkle L
中科院分区：
文献类型：
--
作者：
Kültz D;Li J;Sacchi R;Morin D;Buckpitt A;Van Winkle L
蛋白质加合被认为对于与经历代谢激活的环境化学物质相关的细胞稳态丧失至关重要。尽管付出了巨大的努力，我们对介导亲电子试剂修饰蛋白质的病理后果的关键蛋白质的理解仍然不完整。这项工作的重点是萘诱导的呼吸道上皮细胞急性损伤和多次毒物剂量后出现的耐受性，以确定最初的细胞蛋白质组反应和随后与耐受性相关的保护作用。将暴露于 15 ppm NA 4 小时（急性）或 4 小时/天 × 7 天（耐受）的小鼠的气道和鼻嗅上皮用于通过 LC/MS/MS 进行无标记蛋白质定量。暴露 4 小时的小鼠气道中 Cyp2f2 和分泌球蛋白 1A1 显着减少，这一发现与 P450 主要定位于 Clara 细胞的事实一致。许多热休克蛋白和蛋白质二硫键异构酶先前被确定为几种肺毒物反应性代谢物的加合物靶标，它们在耐受小鼠的气道中上调，但在嗅觉上皮中没有上调。耐受性上调的蛋白质靶标可能是与反应性代谢蛋白加合相关的病理生理学中的关键参与者。
Protein adduction is considered to be critical to the loss of cellular homeostasis associated with environmental chemicals undergoing metabolic activation. Despite considerable effort, our understanding of the key proteins mediating the pathologic consequences from protein modification by electrophiles is incomplete. This work focused on naphthalene-induced acute injury of respiratory epithelial cells and tolerance which arises after multiple toxicant doses to define the initial cellular proteomic response and later protective actions related to tolerance. Airways and nasal olfactory epithelium from mice exposed to 15 ppm NA either for 4 hrs (acute) or for 4 hrs/day × 7 days (tolerant) were used for label free protein quantitation by LC/MS/MS. Cyp2f2 and secretoglobin 1A1 are decreased dramatically in airways of mice exposed for 4 hrs, a finding consistent with the fact that P450’s are localized primarily in Clara cells. A number of heat shock proteins and protein disulfide isomerases, which had previously been identified as adduct targets for reactive metabolites from several lung toxicants, were upregulated in airways but not olfactory epithelium of tolerant mice. Protein targets that are upregulated in tolerance may be key players in the pathophysiology associated with reactive metabolite protein adduction.