Babu Dinesh, Leclercq Georges, Motterlini Roberto, Lefebvre Romain A
Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University Ghent, Belgium.
Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University Ghent, Belgium.
Front Pharmacol. 2017 Feb 8;8:31. doi: 10.3389/fphar.2017.00031. eCollection 2017.
Carbon monoxide (CO)-releasing molecules (CO-RMs) are intensively studied to provide cytoprotective and anti-inflammatory effects of CO in inflammatory conditions including intestinal inflammation. The water-soluble CORM-A1 reduced apoptosis and NADPH oxidase (NOX)-derived reactive oxygen species (ROS) induced by tumor necrosis factor (TNF)-α/cycloheximide (CHX) in mouse MODE-K intestinal epithelial cells (IECs), without influencing TNF-α/CHX-induced mitochondrial superoxide anion ([Formula: see text]). The aim of the present study in the same model was to comparatively investigate the influence of lipid-soluble CORM-2 and water-soluble CORM-401, shown to release more CO under oxidative conditions. CORM-2 abolished TNF-α/CHX-induced total cellular ROS whereas CORM-401 partially reduced it, both partially reducing TNF-α/CHX-induced cell death. Only CORM-2 increased mitochondrial [Formula: see text] production after 2 h of incubation. CORM-2 reduced TNF-α/CHX-, rotenone- and antimycin-A-induced mitochondrial [Formula: see text] production; CORM-401 only reduced the effect of antimycin-A. Co-treatment with CORM-401 during 1 h exposure to HO reduced HO (7.5 mM)-induced ROS production and cell death, whereas CORM-2 did not. The study illustrates the importance of the chemical characteristics of different CO-RMs. The lipid solubility of CORM-2 might contribute to its interference with TNF-α/CHX-induced mitochondrial ROS signaling, at least in mouse IECs. CORM-401 is more effective than other CO-RMs under HO-induced oxidative stress conditions.
一氧化碳释放分子（CO-RMs）受到广泛研究，以在包括肠道炎症在内的炎症条件下发挥CO的细胞保护和抗炎作用。水溶性一氧化碳释放分子A1（CORM-A1）可减少肿瘤坏死因子（TNF）-α/放线菌酮（CHX）诱导的小鼠MODE-K肠上皮细胞（IECs）凋亡和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX）衍生的活性氧（ROS），而不影响TNF-α/CHX诱导的线粒体超氧阴离子（[公式：见原文]）。本研究在同一模型中的目的是比较研究脂溶性一氧化碳释放分子2（CORM-2）和水溶性一氧化碳释放分子401（CORM-401）的影响，这两种分子在氧化条件下能释放更多的CO。CORM-2消除了TNF-α/CHX诱导的总细胞ROS，而CORM-401部分降低了它，两者都部分降低了TNF-α/CHX诱导的细胞死亡。仅CORM-2在孵育2小时后增加了线粒体[公式：见原文]的产生。CORM-2降低了TNF-α/CHX、鱼藤酮和抗霉素A诱导的线粒体[公式：见原文]产生；CORM-401仅降低了抗霉素A的作用。在暴露于次氯酸（HO）1小时期间用CORM-401共同处理可降低HO（7.5 mM）诱导的ROS产生和细胞死亡，而CORM-2则不能。该研究说明了不同CO-RMs化学特性的重要性。CORM-2的脂溶性可能有助于其干扰TNF-α/CHX诱导的线粒体ROS信号传导，至少在小鼠IECs中是这样。在HO诱导的氧化应激条件下，CORM-401比其他CO-RMs更有效。
