The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice.
The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice.
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DOI：
10.1016/j.toxlet.2009.11.016
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发表时间：
2010-02-15
影响因子：
3.5
通讯作者：
Ju, Cynthia
中科院分区：
文献类型：
--
作者：
Martin-Murphy, Brittany V.;Holt, Michael P.;Ju, Cynthia
关键词：
药物性肝损伤（DILI）的特异质性质、严重程度和诊断不佳使这些反应成为药物开发期间的主要安全性问题，也是药物从药品市场撤回的最常见原因。阐明潜在机制对于确定DILI的诱发因素和制定治疗和预防策略是必要的。对乙酰氨基酚（APAP）是一种广泛使用的非处方药，已知在治疗剂量下有效且安全。然而，在过量情况下，可能导致致命和非致命性肝坏死。有证据表明，药物的化学反应性代谢产物会引发肝细胞损伤，并且炎症性先天免疫反应也会发生在肝脏内，导致组织损伤的加重和进展。在这里，我们研究了APAP诱导的肝损伤（AILI）后受损的肝细胞是否释放“危险”信号或损伤相关分子模式分子（DAMP），其诱导肝巨噬细胞的促炎激活，进一步促进肝损伤的进展。我们的研究表明，在早期暴露于APAP（1小时）后，枯否细胞明显活化。小鼠巨噬细胞系RAW细胞的激活，也观察到处理后的肝脏灌注液从APAP处理的小鼠，或与APAP挑战肝细胞的培养上清液。此外，在这些培养基中，DAMP分子，热休克蛋白-70（HSP-70）和高迁移率族蛋白-1（HMGB 1）的检测。总的来说，这些研究结果表明，DAMP分子从受损和坏死的肝细胞释放可能作为一个重要的联系之间的初始肝细胞损伤和先天免疫细胞的激活后APAP暴露，DAMP可能代表一个潜在的治疗靶点AILI。
The idiosyncratic nature, severity and poor diagnosis of drug-induced liver injury (DILI) make these reactions a major safety issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market. Elucidation of the underlying mechanism(s) is necessary for identifying predisposing factors and developing strategies in the treatment and prevention of DILI. Acetaminophen (APAP) is a widely used over the counter therapeutic that is known to be effective and safe at therapeutic doses. However, in overdose situations fatal and non-fatal hepatic necrosis can result. Evidence suggests that the chemically reactive metabolite of the drug initiates hepatocyte damage and that inflammatory innate immune responses also occur within the liver, leading to the exacerbation and progression of tissue injury. Here we investigate whether following APAP-induced liver injury (AILI) damaged hepatocytes release “danger” signals or damage associated molecular pattern molecules (DAMP), which induce pro-inflammatory activation of hepatic macrophages, further contributing to the progression of liver injury. Our study demonstrated a clear activation of Kupffer cells following early exposure to APAP (1hr.). Activation of a murine macrophage cell line, RAW cells, was also observed following treatment with liver perfusate from APAP-treated mice, or with culture supernatant of APAP-challenged hepatocytes. Moreover, in these media, DAMP molecules, heat shock protein-70 (HSP-70) and high mobility group box-1 (HMGB1) were detected. Overall, these findings reveal that DAMP molecules released from damaged and necrotic hepatocytes may serve as a crucial link between the initial hepatocyte damage and the activation of innate immune cells following APAP-exposure, and that DAMPs may represent a potential therapeutic target for AILI.
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影响因子：
4.1
作者：
Ju, C;Reilly, TP;Pohl, LR
通讯作者：
Pohl, LR
影响因子：
29.4
作者：
Liu, ZX;Govindarajan, S;Kaplowitz, N
通讯作者：
Kaplowitz, N
影响因子：
4.8
作者：
Asea, A;Rehli, M;Calderwood, SK
通讯作者：
Calderwood, SK
影响因子：
13.5
作者：
Bourdi, M;Masubuchi, Y;Pohl, LR
通讯作者：
Pohl, LR
DOI：
10.1126/science.1168988
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen GY;Tang J;Zheng P;Liu Y
通讯作者：
Liu Y