Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
J Surg Res. 2011 Jan;165(1):151-7. doi: 10.1016/j.jss.2009.07.008. Epub 2009 Aug 7.
Ethyl pyruvate (EP) has been shown to ameliorate hepatic, renal, and intestinal mucosal injury and down-regulate expression of several pro-inflammatory mediators in a wide variety of preclinical models of critical illnesses, such as sepsis, burn injury, acute pancreatitis, stroke, and hemorrhagic shock. The molecular mechanisms responsible for the therapeutic effects of EP remain poorly understood, but might be related to the compound's structure as the ester of an α-keto carboxylic acid. Herein, we tested the hypothesis that EP and other α-keto carboxylic acid derivatives can modulate organ injury after lower torso ischemia/reperfusion (I/R).
Rats were subjected to 50 min of supraceliac aortic occlusion. Over a 20-min period, starting 2 min before the release of the aortic clamp, the animals received 2 μL/g of Ringer's lactate solution (RL, n = 5) or an equivalent volume of a solution containing EP (n = 5), benzoyl formate (BF, n = 5), parahydroxyphenyl pyruvate (PHPP, n = 5) or sodium pyruvate (NaPyr, n = 5). The total dose of each compound was 0.86 mMol/kg. After 1h of reperfusion, we measured ileal mucosal permeability to fluorescein-labeled dextran (mw 4000 Da), liver malondialdehyde (MDA) content, and plasma levels of alanine aminotransferase (ALT) and TNF. Rats in the control group (CT, n = 4) were subjected to laparotomy and surgical isolation of the supraceliac aorta, but not visceral I/R.
Ileal mucosal permeability, plasma levels of ALT and TNF, and hepatic MDA content increased significantly in the RL group relative to the CT group. Both EP and BF significantly ameliorated the development of systemic arterial hypotension, mucosal hyperpermeability, and significantly decreased plasma levels of TNF. MDA content was significantly decreased by EP, PHPP, BF, and NaPyr.
In general, EP is more efficacious in this model than is NaPyr. Although more remains to be learned about the pharmacologic differences between EP and pyruvate, one important factor may the greater lipophilicity of the former compound. This insight may permit the development of even more effective cytoprotective and anti-inflammatory agents based on the pyruvoyl moiety.
已证实乙基丙酮酸（EP）可改善肝、肾和肠黏膜损伤，并下调多种危重病临床前模型（如败血症、烧伤、急性胰腺炎、中风和失血性休克）中几种促炎介质的表达。EP 发挥治疗作用的确切分子机制尚不完全清楚，但可能与该化合物作为α-酮羧酸的酯的结构有关。在此，我们检验了以下假说，即 EP 和其他α-酮羧酸衍生物可调节下半身缺血/再灌注（I/R）后的器官损伤。
大鼠接受 50 分钟的腹腔上主动脉阻断。在释放主动脉夹 2 分钟前的 20 分钟期间，动物接受 2μL/g 的林格氏乳酸盐溶液（RL，n=5）或含有 EP（n=5）、苯甲酰甲酸（BF，n=5）、对羟基苯丙酮酸（PHPP，n=5）或丙酮酸钠（NaPyr，n=5）的等容量溶液。每种化合物的总剂量为 0.86mMol/kg。再灌注 1 小时后，我们测量了荧光素标记的右旋糖酐（mw4000Da）通过回肠黏膜的通透性、肝丙二醛（MDA）含量以及血浆丙氨酸氨基转移酶（ALT）和 TNF 的水平。在对照组（CT，n=4）中，大鼠接受剖腹术和腹腔上主动脉的外科分离，但不进行内脏 I/R。
与 CT 组相比，RL 组大鼠回肠黏膜通透性、血浆 ALT 和 TNF 水平以及肝 MDA 含量显著增加。EP 和 BF 均显著改善了全身动脉低血压、黏膜高通透性的发展，并显著降低了 TNF 的血浆水平。EP、PHPP、BF 和 NaPyr 均显著降低 MDA 含量。
一般来说，EP 在该模型中的疗效优于 NaPyr。尽管 EP 和丙酮酸之间的药理学差异还有待进一步了解，但一个重要因素可能是前者化合物的疏水性更强。这一见解可能允许基于丙酮酸基开发更有效的细胞保护和抗炎药物。
