Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK.
BMC Gastroenterol. 2010 Mar 30;10:34. doi: 10.1186/1471-230X-10-34.
The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF.
35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased.
Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n = 4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8 +/- 5.9 vs 59 +/- 2.0 mmHg), increased cardiac output (7.26 +/- 1.86 vs 3.30 +/- 0.40 l/min) and decreased systemic vascular resistance (8.48 +/- 2.75 vs 16.2 +/- 1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636 +/- 95 vs 301 +/- 26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome.Liver damage was confirmed by deterioration in pH (7.23 +/- 0.05 vs 7.45 +/- 0.02) and prothrombin time (36 +/- 2 vs 8.9 +/- 0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5 +/- 210 vs 42 +/- 8.14) coincided with a marked reduction in serum albumin (11.5 +/- 1.71 vs 25 +/- 1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2 +/- 36.5 vs 131.6 +/- 9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06.
We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems.
急性肝衰竭（ALF）的有效治疗方法的发展受到我们对这种疾病病理生理学的了解的限制，以及缺乏合适的大动物模型来模拟对乙酰氨基酚毒性。我们的目的是开发一种可重复的、有创监测的猪模型，用于研究对乙酰氨基酚诱导的 ALF。
35kg 猪在全身麻醉下接受有创监测。对照组猪接受生理盐水输注，而 ALF 组猪则接受静脉注射对乙酰氨基酚 12 小时，以维持血液浓度在 200-300mg/l 之间。存活 28 小时的动物被安乐死。
苯巴比妥预处理动物的细胞色素 p450 水平明显高于未预处理动物（300 比 100 pmol/mg 蛋白）。接受生理盐水输注的对照组猪（n=4）在 28 小时麻醉期间没有出现任何意外。在接受对乙酰氨基酚治疗的 9 只猪中，有 4 只存活了 20 小时，2 只存活了 28 小时。受伤的动物出现低血压（平均动脉压；40.8 +/- 5.9 比 59 +/- 2.0mmHg）、心输出量增加（7.26 +/- 1.86 比 3.30 +/- 0.40l/min）和全身血管阻力降低（8.48 +/- 2.75 比 16.2 +/- 1.76mPa/s/m3）。随着肝损伤的进展，呼吸困难发展，观察到的增加的肺血管阻力（636 +/- 95 比 301 +/- 26.9mPa/s/m3）可能反映了呼吸窘迫综合征的发展。与对照组相比，pH 值（7.23 +/- 0.05 比 7.45 +/- 0.02）和凝血酶原时间（36 +/- 2 比 8.9 +/- 0.3 秒）的恶化证实了肝损伤。受伤动物的因子 V 和 VII 水平分别降至起始值的 9.3%和 15.5%。血清天冬氨酸转氨酶（AST）显著升高（471.5 +/- 210 比 42 +/- 8.14），同时血清白蛋白（11.5 +/- 1.71 比 25 +/- 1g/dL）显著降低。动物表现出肾功能损害的证据；肌酐水平为 280.2 +/- 36.5 比 131.6 +/- 9.33umol/l。肝组织学显示出严重的中央小叶坏死伴凝固性坏死的证据。还观察到明显的肾小管坏死。高铁血红蛋白水平没有升高超过 5%。未出现颅内压升高（ICP 监测），但 Fischer 比值从 5.6 +/- 1.1 降至 0.45 +/- 0.06，表明存在肝性脑病的生化证据。
我们已经开发了一种可重复的、大动物模型，用于研究对乙酰氨基酚诱导的肝衰竭，这允许深入研究这种疾病的病理生理学基础。此外，这代表了一种重要的大动物模型，用于测试人工肝支持系统。
