Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Friedrich-Schiller-University Jena, Jena 07747, Germany; Department of Pathophysiology, Anhui Medical University, Hefei 236000, China.
Cytokine. 2013 Oct;64(1):71-8. doi: 10.1016/j.cyto.2013.07.025. Epub 2013 Aug 16.
Lipopolysaccharide (LPS) binding protein (LBP) is an acute phase protein, which upregulated in response to surgical interventions. LBP plays an important role in modulating LPS-induced inflammatory response. We investigated the expression of LBP and the translocation of LPS in rat models of hepatic ischemia reperfusion injury and liver transplantation (LTx). We also elucidated the effect of LBP on the inflammatory response.
In this study, cold ischemia (CI), warm ischemia/reperfusion (WI/R), and LTx models were used to model relevant physiologic situations during LTx. Serum and effluent protein levels as well as hepatic-mRNA and protein levels of LBP were examined. LBP released into the effluent during CI was used in a macrophage-LPS-stimulation assay to investigate the role of LBP in modulating the LPS-induced inflammatory response. Blocking experiments using an LBP-inhibitory peptide were performed to confirm the relevance of LPS/LBP for the induction of the inflammatory response. Impairment of the intestinal barrier and translocation of LPS into the liver was visualized by immunohistochemistry. Induction of tumor necrosis factor-alpha (TNF-α) mRNA expression in the liver was taken as indicator of the inflammatory response.
Upregulation of LBP in serum and/or liver tissue was observed after WI/R, CI and LTx, respectively. The LBP released during CI enhanced the LPS induced inflammatory response in vitro as indicated by an induction of TNF-α. On the other hand, blocking LBP using LBP inhibitory peptide, suppressed the induction of TNF-α in vitro markedly. After LTx, elevated serum LBP levels were associated with post-operative LPS translocation and production of inflammatory cytokines.
Our findings suggest that translocation of LPS occurs after LTx and that LBP is mediating the LPS-induced inflammatory response after LTx. Blocking LBP using LBP-inhibitory peptide might represent a novel strategy to reduce the I/R-induced inflammatory response.
脂多糖结合蛋白（LBP）是一种急性时相蛋白，可响应手术干预而上调。LBP 在调节 LPS 诱导的炎症反应中发挥重要作用。我们研究了肝缺血再灌注损伤和肝移植（LTx）大鼠模型中 LBP 的表达和 LPS 的易位。我们还阐明了 LBP 对炎症反应的影响。
在这项研究中，使用冷缺血（CI）、温缺血/再灌注（WI/R）和 LTx 模型来模拟 LTx 过程中的相关生理情况。检测血清和流出物蛋白水平以及肝 LBP 的 mRNA 和蛋白水平。在 CI 期间释放到流出物中的 LBP 用于巨噬细胞-LPS 刺激测定，以研究 LBP 在调节 LPS 诱导的炎症反应中的作用。使用 LBP 抑制肽进行阻断实验，以确认 LPS/LBP 与诱导炎症反应的相关性。通过免疫组织化学观察肠屏障的损伤和 LPS 易位到肝脏。诱导肝肿瘤坏死因子-α（TNF-α）mRNA 表达作为炎症反应的指标。
分别在 WI/R、CI 和 LTx 后观察到血清和/或肝组织中 LBP 的上调。在 CI 期间释放的 LBP 增强了体外 LPS 诱导的炎症反应，如 TNF-α 的诱导所示。另一方面，使用 LBP 抑制肽阻断 LBP 显著抑制了体外 TNF-α的诱导。在 LTx 后，升高的血清 LBP 水平与术后 LPS 易位和炎症细胞因子的产生相关。
我们的发现表明，LTx 后发生 LPS 易位，LBP 介导 LTx 后 LPS 诱导的炎症反应。使用 LBP 抑制肽阻断 LBP 可能代表一种减少 I/R 诱导的炎症反应的新策略。
