Inflammation, SIRS and Sepsis after hepatobiliary surgery: is lipopolysaccharide binding protein the link?

Background: LBP binds to LPS and activates an inflammatory cascade. LBP is an acute phase protein, which is currently investigated as marker of sepsis. LBP is upregulated by LPS and in infectious diseases, but also after major surgery. Extended liver resection may be fatal due to the development of liver failure. Liver failure is associated with LPS and bacterial translocation. LPS as well as bacterial translocation represents a major risk for developing systemic inflammatory response syndrome (SIRS) and sepsis after extended liver resection. We previously demonstrated that LBP-upregulation after G-CSF pretreatment improved the outcome in the lethal model of 90% PH using the mass ligation technique. We want to understand the role of LBP in postoperative inflammation, SIRS and sepsis. We established a novel LBP-ELISA assay to first determine the expression level after hepatobiliary procedures. Second, we tested the effect of LBP upregulation in a SIRS and third in a Sepsis model. Method: An LBP-ELISA assay was established based on the binding between LPS and LBP. 1. Liver samples and serums were obtained after different degrees of PH, WI/R and LTx to investigate LBP expression, liver injury and the expression of pro-inflammatory cytokines. LBP released into the effluent during CI was used in a macrophage-LPS-stimulation assay to investigate the role of LBP in vitro. Blocking experiments using an LBP-inhibitory peptide were performed to confirm the relevance of LPS/LBP for the induction of the inflammatory response. 2. After pretreatment with G-CSF to upregulate LBP-expression, rats were subjected to subsequent LPS challenge with or without 70% PH. LBP inhibitory peptide was used to block the interaction between LBP and LPS. Serum and hepatic LBP levels, mortality, hepatic injury (AST, histological evaluation), and inflammatory cytokines were used to assess the severity of inflammatory response. LPS IHC staining was performed to observe the time-dependent process of LPS-binding in the liver. 3. The role of GCSF-induced LBP-upregulation was also investigated in poly-microbial sepsis in naive rats. Mortality, hepatic injury (AST, histological evaluation), and inflammatory cytokines were used to assess the severity of inflammatory response. Results: (1) LBP elevation was related to the size and thereby the synthetic capacity of the small remnant liver after liver resection. Translocation of LPS and upregulation of LBP occured after LTx, but also after PH and WI/R and was associated with the postoperative inflammatory response after LTx. (2) Pre-operative upregulation of LBP via G-CSF sensitized to a subsequent LPS challenge and enhanced the LPS-induced inflammatory response. In contrast, blocking the interaction between LBP and LPS attenuated the overt inflammatory response. (3) Pretreatment with G-CSF attenuated the inflammation in the poly-microbial sepsis model. We speculated that LBP-blocking peptide would aggravate the outcome in sepsis. Conclusion: Taken together, LBP was increased and modulated the inflammation after liver surgery. Blocking LBP using LBP-inhibitory peptide might represent a novel strategy to reduce the I/R-induced inflammatory response. G-CSF induced LBP expression aggravated the clinical course in LPS-induced SIRS and but had a protective effect in poly-microbial sepsis. These seemingly contradictory results suggest, that the effect of LBP is dependent on the type of inflammatory/infectious insult and the phase of disease. Our findings may help to explain the limited value of LBP-levels as diagnostic and predictive marker of SIRS and sepsis when determined after the insult. However, LBP levels may be potentially useful to assess the risk when measured prior to the defined insult.