University of Michigan Medical School, Ann Arbor, 49109, USA.
Am J Physiol Gastrointest Liver Physiol. 2010 Dec;299(6):G1319-25. doi: 10.1152/ajpgi.00140.2010. Epub 2010 Sep 16.
Acetaminophen (APAP)-induced liver injury remains the main cause of acute liver failure in the United States. Our previous work demonstrated that LPS binding protein (LBP) knockout mice are protected from APAP-induced hepatotoxicity. LBP is known to bind avidly to LPS, facilitating cellular activation. In this study, we sought to specifically inhibit the interaction between LBP and LPS to define the role of this interaction in APAP-induced liver injury. The peptide LBPK95A was able to inhibit LBP-mediated LPS activation of RAW 267.4 cells in a dose-dependent manner in vitro. In vivo, C57Bl/6 mice were treated with either LBPK95A or vehicle control concurrently with the administration of APAP (350 mg/kg). Mice treated with LBPK95A had significantly lower serum aspartate aminotransferase and alanine aminotransferase levels. Morphometric analysis of the liver tissue showed significantly less liver injury in mice treated with LBPK95A. To assess whether the LBPK95A altered glutathione depletion and APAP metabolism, we measured total glutathione levels in the liver after APAP. We found no difference in the glutathione levels and APAP-adduct formation between LBPK95A vs. vehicle control both at baseline and after APAP. In conclusion, our results support the hypothesis that LBP-induced liver injury after APAP is due to its ability to mediate activation by endogenous LPS. Our results suggest that blocking LBP-LPS interactions is a potential therapeutic avenue for the treatment of APAP-induced liver injury.
对乙酰氨基酚（APAP）诱导的肝损伤仍然是美国急性肝衰竭的主要原因。我们之前的工作表明，脂多糖结合蛋白（LBP）敲除小鼠对 APAP 诱导的肝毒性具有保护作用。已知 LBP 能与 LPS 紧密结合，促进细胞活化。在这项研究中，我们试图专门抑制 LBP 与 LPS 之间的相互作用，以确定这种相互作用在 APAP 诱导的肝损伤中的作用。肽 LBPK95A 能够在体外以剂量依赖性方式抑制 LBP 介导的 RAW 267.4 细胞中 LPS 的激活。在体内，C57Bl/6 小鼠在用 APAP（350mg/kg）给药的同时用 LBPK95A 或载体对照进行治疗。用 LBPK95A 治疗的小鼠血清天冬氨酸转氨酶和丙氨酸转氨酶水平明显较低。对肝组织的形态计量学分析显示，用 LBPK95A 治疗的小鼠肝损伤明显较少。为了评估 LBPK95A 是否改变了谷胱甘肽耗竭和 APAP 代谢，我们在 APAP 后测量了肝组织中的总谷胱甘肽水平。我们发现，在用 LBPK95A 与载体对照进行治疗时，在基线和 APAP 后，谷胱甘肽水平和 APAP 加合物形成均无差异。总之，我们的结果支持这样的假设，即 APAP 后 LBP 诱导的肝损伤是由于其介导内源性 LPS 激活的能力。我们的结果表明，阻断 LBP-LPS 相互作用是治疗 APAP 诱导的肝损伤的一种潜在治疗途径。
