Salhanick Steven D, Belikoff Bryan, Orlow Daniel, Holt Douglas, Reenstra Wende, Buras Jon A
Program in Toxicology, Division of Emergency Medicine, Children's Hospital, Boston, MA, USA.
Acad Emerg Med. 2006 Jul;13(7):707-14. doi: 10.1197/j.aem.2006.01.029. Epub 2006 Apr 24.
To investigate the effect of hyperbaric oxygen (HBO2) on acetaminophen (APAP)-induced hepatotoxicity. The authors further evaluated the effects of APAP poisoning and HBO2 on the expression and function of hypoxia-inducible factor 1-alpha (HIF-1alpha) in an effort to further describe the mechanisms of APAP-induced hepatotoxicity. In vitro assays were performed to better understand the effects of HBO2 on HIF-1alpha function.
In vivo, four groups of C57BL/6 mice were treated as follows: APAP only, APAP followed by HBO2, HBO2 only, and untreated shams. Plasma alanine aminotransferase activity was measured, and hepatic HIF-1alpha induction was determined by Western blot. In vitro, cultured HEP G2 hepatocytes were exposed to HBO2, hypoxia (2.5% O2), or normoxia. HIF-1alpha DNA-binding and transcriptional activity were assessed.
Alanine aminotransferase activity was reduced in the APAP+HBO2 group (2,606 IU/L +/- 4,080; vs. APAP: 6,743 +/- 3,397, p = 0.01 at 6 hours). APAP-only, HBO2-only, and APAP+HBO2 treatments all increased HIF-1alpha expression relative to shams (p = 0.02, p = 0.02, and p < 0.01, respectively). HBO2 increased HIF-1alpha DNA binding 5.7 (+/- 1.2)-fold relative to controls (p < 0.01); however, a parallel increase in HIF functional transcriptional activity did not occur.
Hyperbaric oxygen reduced early APAP-induced hepatocellular injury. APAP poisoning increases HIF-1alpha protein levels and functional activity. HBO2 increases HIF-1alpha protein levels and DNA binding without a corresponding increase in transcriptional activity.
研究高压氧（HBO₂）对乙酰氨基酚（APAP）诱导的肝毒性的影响。作者进一步评估了APAP中毒和HBO₂对缺氧诱导因子1α（HIF-1α）表达和功能的影响，以进一步描述APAP诱导肝毒性的机制。进行体外试验以更好地了解HBO₂对HIF-1α功能的影响。
在体内，将四组C57BL/6小鼠按以下方式处理：仅给予APAP、给予APAP后再给予HBO₂、仅给予HBO₂以及未处理的假手术组。测量血浆丙氨酸氨基转移酶活性，并通过蛋白质印迹法测定肝脏中HIF-1α的诱导情况。在体外，将培养的人肝癌细胞系（HEPG2）肝细胞暴露于HBO₂、低氧（2.5%氧气）或常氧环境中。评估HIF-1α的DNA结合和转录活性。
APAP+HBO₂组的丙氨酸氨基转移酶活性降低（2,606 IU/L±4,080；与APAP组相比：6,743±3,397，6小时时p = 0.01）。相对于假手术组，仅给予APAP组、仅给予HBO₂组和APAP+HBO₂组均增加了HIF-1α的表达（分别为p = 0.02、p = 0.02和p < 0.01）。相对于对照组，HBO₂使HIF-1α的DNA结合增加了5.7（±1.2）倍（p < 0.01）；然而，HIF功能转录活性并未出现平行增加。
高压氧减轻了早期APAP诱导的肝细胞损伤。APAP中毒增加了HIF-1α蛋白水平和功能活性。HBO₂增加了HIF-1α蛋白水平和DNA结合，但转录活性并未相应增加。
