Inducer of heme oxygenase-1 cobalt protoporphyrin accelerates autophagy and suppresses oxidative damages during lipopolysaccharide treatment in rat liver
Inducer of heme oxygenase-1 cobalt protoporphyrin accelerates autophagy and suppresses oxidative damages during lipopolysaccharide treatment in rat liver
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DOI：
10.1111/j.1872-034x.2012.01049.x
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发表时间：
2013-01-01
影响因子：
4.2
通讯作者：
Uemura, Koichi
中科院分区：
文献类型：
--
作者：
Unuma, Kana;Aki, Toshihiko;Uemura, Koichi
目的：线粒体损伤和随后的氧化应激在脓毒症诱导的器官衰竭的发病机制中起重要作用。最近，自噬作为线粒体质量控制的主要降解途径，被报道为细胞对氧化应激的适应性反应。本研究的目的是阐明脂多糖（LPS）治疗过程中肝损伤的分子机制。我们还试图确定是否可以通过施用钴原卟啉（CoPP），一种有效的血红素加氧酶-1 （HO-1）诱导剂来减轻损伤。方法：5周龄雄性SpragueDawley大鼠腹腔注射LPS 15 mg/kg。为了确定HO-1是否能减轻LPS给药后的肝损伤，以24小时为间隔连续4天注射CoPP。LPS处理后，取肝脏进行分析。结果：lps处理大鼠肝脏线粒体蛋白大量减少，自噬诱导。电镜和免疫组织化学分析显示lps处理的大鼠肝脏中存在自噬空泡。脂多糖处理动物的氧化应激标志物（4-羟基-2-壬烯醛和8-羟基-2'-脱氧鸟苷）升高；CoPP治疗消除了这些改变。环孢素A是线粒体通透性过渡孔开放的抑制剂，可抑制LPS给药过程中的氧化应激和肝脏损伤。CoPP促进大鼠自噬，防止LPS对肝脏的损害。结论：HO-1促进lps处理大鼠肝脏的自噬和受损线粒体的消除，从而抑制氧化应激，揭示了HO-1保护脓毒性肝损伤的新机制。
Aim: Mitochondrial damage and subsequent oxidative stresses play important roles in the pathogenesis of sepsis-induced organ failure. Recently, autophagy, the major degradation pathway involved in mitochondrial quality control, was reported as a cellular adaptive response to oxidative stresses. The aim of the present study was to elucidate the molecular mechanism that underlies hepatic damage during lipopolysaccharide (LPS) treatment. We also try to determine if the damage can be attenuated by administration of cobalt protoporphyrin (CoPP), a potent heme oxygenase-1 (HO-1) inducer. Methods: Five-week-old male SpragueDawley rats were injected i.p. with 15 mg/kg LPS. To determine if hepatic damage following LPS administration can be attenuated by HO-1, CoPP was injected s.c. for 4 days consecutively at 24-h intervals. After treatment with LPS, the liver was obtained and analyzed. Results: A large reduction in liver mitochondrial protein and induction of autophagy were observed in LPS-treated rats. Electron microscopic and immunohistochemical analyses demonstrated autophagic vacuoles in LPS-treated rat liver. Oxidative stress markers (4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine) were increased in LPS-treated animals; CoPP treatment ablated these alterations. An inhibitor for the opening of mitochondrial permeability transition pore, cyclosporine A, suppressed oxidative stress as well as liver damage during LPS administration. CoPP promoted autophagy and prevented rats from liver damage during LPS administration. Conclusion: HO-1 promotes autophagy and elimination of damaged mitochondria thereby repressing oxidative stress in LPS-treated rat liver, revealing a novel mechanism for protection by HO-1 against septic liver damage.