Department of Pharmaceutical Sciences, University of Colorado Denver, Denver, CO, USA.
Toxicol Lett. 2010 Apr 15;194(1-2):34-41. doi: 10.1016/j.toxlet.2010.01.020. Epub 2010 Feb 1.
Although there has been considerable research in terms of liver sinusoidal endothelial cells (LSECs) and hepatic resident macrophages (Kupffer cells, KCs) during the overall pathogenesis of acetaminophen (APAP)-induced liver injury, little is known about their potential interaction and relationship. In the present study, employing the use of liposome/clodronate to deplete KCs, we were able to confirm the previously demonstrated hepato-protective role for KCs. Such a protective role may be mediated, in part, via regulation of LSEC homeostasis and integrity. The further aggravation of APAP-induced LSEC disturbance upon depletion of KCs correlated with increased hepatic vascular permeability and red blood cell accumulation. The depletion of KCs prior to APAP challenge also resulted in the increased expression of cellular adhesion molecules on LSECs. Such increased disturbance in the hepatic endothelial may represent a contributing factor in the exacerbation of APAP-induced liver injury in the absence of KCs. However, these disturbances may also be a result of the increased hepatic damage, and as such, does not rule out the potential for additional mechanisms of KC-mediated hepato-protection during the pathogenesis of APAP-induced hepatotoxicity.
虽然在对乙酰氨基酚（APAP）诱导的肝损伤的整体发病机制中，已经对肝窦内皮细胞（LSEC）和肝固有巨噬细胞（库普弗细胞，KCs）进行了相当多的研究，但它们之间的潜在相互作用和关系知之甚少。在本研究中，我们使用脂质体/氯膦酸盐来耗尽 KCs，从而能够证实先前证明的 KCs 对肝脏的保护作用。这种保护作用可能部分是通过调节 LSEC 的稳态和完整性来介导的。在耗尽 KCs 后，APAP 诱导的 LSEC 紊乱进一步加重，与肝血管通透性增加和红细胞积聚相关。在 APAP 攻击前耗尽 KCs 也导致 LSEC 上细胞黏附分子的表达增加。这种肝内皮的紊乱增加可能是在没有 KCs 的情况下加剧 APAP 诱导的肝损伤的一个促成因素。然而，这些紊乱也可能是肝损伤增加的结果，因此，不能排除 KC 介导的肝保护在 APAP 诱导的肝毒性发病机制中的其他潜在机制。
