Ohara N, Voelkel N F, Chang S W
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver 80262.
Hepatology. 1993 Jul;18(1):111-8.
Advanced cirrhosis is known to be associated with extrahepatic organ dysfunction, but the mechanism for this cirrhosis complication is largely unknown. We measured tissue albumin leakage in rats with biliary cirrhosis or acute cholestasis and tested the hypothesis that arachidonic acid metabolites contribute to the vascular permeability change. Six weeks after bile duct ligation, rats with biliary cirrhosis exhibited increased extravascular leakage of 125I-albumin in lung (p < 0.001) and kidney (p < 0.01) but not in heart or brain. In contrast, in cholestatic rats 10 days after bile duct ligation, only the kidney albumin leak was significantly increased (p < 0.01). Tissue thromboxane B2 levels, measured with an enzyme immunoassay, were increased in lung, kidney and liver of cirrhotic and cholestatic rats. To determine whether thromboxane A2 contributes to the vascular permeability defects in cirrhosis, we pretreated cirrhotic rats with the thromboxane synthase inhibitor dazoxiben (10 mg/kg intraperitoneally every 8 hr) for 20 hr before assessment of vascular permeability. Dazoxiben blocked the increase in thromboxane B2 level in lung but not in kidney and lowered the lung but not the kidney albumin leak index. In cholestatic rats given a higher dose of dazoxiben (40 mg/kg intraperitoneally every 8 hr) for 20 hr, the kidney thromboxane B2 level but not albumin leak was significantly lowered. We conclude that chronic biliary obstruction in rats leads to increased vascular permeability in selected extrahepatic organs and that thromboxane A2 contributes to the vascular permeability increase in the lung. Whether thromboxane A2 plays a role in renal albumin leakage will require further study.
已知晚期肝硬化与肝外器官功能障碍有关，但这种肝硬化并发症的机制在很大程度上尚不清楚。我们测量了胆汁性肝硬化或急性胆汁淤积大鼠的组织白蛋白渗漏情况，并检验了花生四烯酸代谢产物导致血管通透性改变这一假说。胆管结扎六周后，胆汁性肝硬化大鼠肺（p < 0.001）和肾（p < 0.01）中125I - 白蛋白的血管外渗漏增加，但心脏和大脑未出现这种情况。相比之下，在胆管结扎10天后的胆汁淤积大鼠中，只有肾白蛋白渗漏显著增加（p < 0.01）。用酶免疫测定法测得的组织血栓素B2水平在肝硬化和胆汁淤积大鼠的肺、肾和肝脏中均升高。为了确定血栓素A2是否导致肝硬化中的血管通透性缺陷，我们在评估血管通透性前20小时，用血栓素合酶抑制剂达唑氧苯（每8小时腹腔注射10 mg/kg）对肝硬化大鼠进行预处理。达唑氧苯可阻止肺中血栓素B2水平升高，但不能阻止肾中血栓素B2水平升高，并且降低了肺白蛋白渗漏指数，但未降低肾白蛋白渗漏指数。在每8小时腹腔注射更高剂量达唑氧苯（40 mg/kg）20小时的胆汁淤积大鼠中，肾血栓素B2水平显著降低，但白蛋白渗漏未降低。我们得出结论，大鼠慢性胆管梗阻导致特定肝外器官的血管通透性增加，并且血栓素A2导致肺血管通透性增加。血栓素A2是否在肾白蛋白渗漏中起作用尚需进一步研究。
