Lipopolysaccharide binding protein in cirrhotic patients with severe sepsis : Journal of the Chinese Medical Association

Secondary Logo

Journal Logo

Original Article

Lipopolysaccharide binding protein in cirrhotic patients with severe sepsis

Chen, Yi-Yuana,e; Lien, Jau-Mina,e; Peng, Yun-Shingb,e; Chen, Yung-Changc,e; Tian, Ya-Chungc,e; Fang, Ji-Tsengc,e; Huang, Hsing-Chiha,e; Chen, Pang-Chia,e; Yang, Chih-Weic,e; Wu, Cheng-Shyongd,e; Tsai, Ming-Hunga,e,*

Author Information
Journal of the Chinese Medical Association: February 2014 - Volume 77 - Issue 2 - p 68-74
doi: 10.1016/j.jcma.2013.10.006

    Abstract

    1. Introduction

    Cirrhotic patients are susceptible to bacterial infection, which can lead to multiple organ dysfunction and decreased survival.1–4 Lipopolysaccharide (LPS), a component of the cell membrane of Gram-negative bacteria, plays a central role in the pathophysiology of sepsis.5,6 In response to endotoxin challenge, cirrhotic patients show an augmented capacity to produce pro-inflammatory cytokines, 7−10 which may be linked to multiple organ dysfunction in severe sepsis. Despite advances in intensive care, the prognosis for severe sepsis in liver cirrhosis is still poor.11,12 Recognition of bacterial components by the innate immune system is an important event for triggering the inflammatory response, which is necessary to eliminate the invading microorganisms. Lipopolysaccharide-binding protein (LBP) is a 58-kDa protein that potently enhances the sensitivity of monocytes and granulocytes to LPS by facilitating binding of LPS to the CD14 cell membrane molecule and Toll-like receptor 4, activating the innate immune system by releasing inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).5,6 In several clinical settings, serum LBP seems to better reflect the long-term exposure to bacteria and their endotoxins than endotoxin itself.13–15 In fact, in cirrhotic patients without bacterial infection, increased levels of LBP can identify a subset of ascitic cirrhotic patients with increased levels of cytokines and a more pronounced vasodilatation.15 However, LBP mediates LPS transfer to high-density lipoprotein (HDL) particles, leading to neutralization of LPS.16,17 Taken together, LBP may have dual effects in terms of modulation of the innate immune response.18 Indeed, it has been shown that LBP plays a concentration-dependent dual role in the pathogenesis of sepsis. Low levels of LBP enhance the LPS-induced activation of mononuclear cells (MNC), whereas the acute-phase rise in LBP concentrations inhibits LPS-induced cellular stimulation.18,19 After the pathophysiological role of LBP was unraveled, the diagnostic and prognostic values of LBP in patients with systemic inflammatory response syndrome (SIRS) and sepsis have been evaluated. Although the levels of LBP have been consistently high in patients with SIRS and sepsis,13,20 the diagnostic and prognostic values of LBP in different clinical settings have been conflicting.13,20,21 The reason for these discrepancies is unclear and probably due to heterogeneity of patient groups.

    Like many other acute phase proteins, LBP is mainly synthesized in the liver.22 Accordingly, upregulation of LBP may be compromised in case of impaired synthetic capacity of the liver, making the interpretation difficult. Severe sepsis can precipitate acute or chronic liver failure in cirrhotic patients and induce a wide array of metabolic and immunological abnormalities.23,24 Although the clinical relevance of LBP has been shown in stable cirrhotic patients without bacterial infection,15 the prognostic significance of LBP has never been evaluated in cirrhotic patients with severe sepsis. Considering the impaired biosynthesis of LBP in cirrhotic liver and the bipolar role that LBP plays in innate immunity, the prognostic values of LBP in cirrhotic patients with severe sepsis may be quite different from those of other clinical entities. Therefore, we conducted this prospective observational study to investigate whether the levels of LBP are associated with poor outcomes in patients with liver cirrhosis and severe sepsis. Other potential indicators of inflammation such as c-reactive protein (CRP), TNF-α, and IL-6 were also measured.

    2. Methods

    2.1. Patient information, data collection, and definitions

    This study was conducted with the approval of the institutional review board of Chang Gung Memorial Hospital, Taiwan. Formal consent was obtained from the next of kin. The study enrolled 58 consecutive cirrhotic patients with severe sepsis requiring intensive monitoring and/or treatment. Severe sepsis was defined by the criteria of the American College of Chest Physicians/Society of Critical Care Medicine,25 namely sepsis associated with organ dysfunction, hypoperfusion abnormality, or sepsis-induced hypotension. Liver cirrhosis was defined histologically or based on clinical, image, and laboratory findings. All patients were treated with a standard treatment protocol for management of severe sepsis and septic shock.26 Management included early targeted resuscitation, broad empiric antibiotic coverage, infection source control, and effective shock evaluation and treatment. The empiric antibiotic therapy was as previously described.12,27 The empiric antibiotic regimen was modified on the basis of microbiological data. The major outcome analyzed was 28-day mortality.

    The severity of liver disease on the day of blood sampling was graded by the Child-Pugh and Model for End-stage Liver Disease (MELD) scores.28,29 Meanwhile, multiple organ dysfunction also was assessed by sequential organ failure assessment (SOFA) scores.30–32 For these scoring systems and physiological evaluations, the most abnormal value for each organ system on the day of blood sampling was recorded.

    Bacteremia was defined as the presence of viable bacteria in the blood,25 as evidenced by a positive blood culture. Spontaneous bacteremia was defined as bacteremia without identified infection focus. Culture-negative sepsis was defined as the presence of systemic inflammatory response syndrome (SIRS)25 and negative cultures after exclusion of the possibility of non-infection inflammatory conditions as the causes of SIRS.

    2.2. Laboratory investigations

    Blood cultures and appropriate cultures from the infection focus were obtained. Hematological and biochemical data were also collected systemically within 24 hours of admission to ICU.

    Fasting blood samples were obtained in the morning. The blood samples were allowed to clot and were spun immediately in a refrigerated centrifuge. The serum was obtained and frozen at −80 °C. LBP was measured by an enzyme-linked immunosorbent assay (Cell Sciences, Inc, Canton, MA). The concentrations of TNF-α and IL-6 were measured by an enzyme-linked immunosorbent assay (R & D Systems, Minneapolis, MN). C-reactive protein was measured by a latex-enhanced immunoturbidimetric method (Daiichi Pure Chemical, Ibaraki, Japan).

    2.3. Statistical analysis

    Descriptive statistics are expressed as mean ± SD. All variables were tested for normal distribution using the Kolmogorov-Smirnov test. Student's t test was used to compare the means of continuous variables and the normal distribution data. Otherwise, the Mann-Whitney U test was used. Categorical data were tested using the Chi-square (χ2) test. The correlation between LBP levels and disease severity scores was analyzed with linear regression using the Pearson method. Discrimination was tested using the area under a receiver operating characteristic (ROC) curve33 to assess the ability of LBP to predict 28-day mortality. ROC analysis was also performed to calculate the cut-off values, sensitivity, specificity, overall correctness, and positive and negative predictive values. The best Youden index (sensitivity + specificity – 1)34 was also used to determine the best cut-off point of LBP to predict 28-day mortality. All statistical tests were two-tailed, and the significance level was set at p = 0.05 or less. Data were analyzed using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, USA).

    3. Results

    3.1. Patients' characteristics

    Fifty-eight critically ill cirrhotic patients were enrolled in this investigation. The cause of liver cirrhosis was hepatitis B virus (HBV) in 26 patients, alcohol in 17, hepatitis C virus (HCV) in nine, HBV plus alcohol in two, HBV plus HCV in three, and an unknown cause in one. Overall, the ICU and 28-day mortality rates for the entire group were 58.6% and 62.1%, respectively. Table 1 lists the patients' demographic data and clinical characteristics. Compared to survivors, the non-survivors had higher disease severity and poorer liver reserve as evidenced by higher SOFA, MELD, and Child-Pugh scores. Microbiological information was available for all patients. Fifty-two patients had at least one positive microbiological culture. Positive cultures were obtained from the blood in 27 (46.5%) patients, from urine in 16 (27.5%), from sputum in 18 (31.0%), from ascites in 16 (27.5%) patients, and from a CVP catheter tip in two (3.4%).

    T1-4
    Table 1:
    Patients' demographic data and clinical characteristics grouped according to 28-day mortality.

    3.2. Concentrations of LBP and cytokines

    The levels of LBP were significantly higher in those who survived (Table 1), while the levels of TNF-α and IL-6 were higher in those who died. Low levels of LBP were associated with higher levels of TNF-α (Table 2). The levels of LBP were inversely correlated with Child-Pugh, MELD, and SOFA scores (Fig. 1).

    T2-4
    Table 2:
    Patients' demographic data and clinical characteristics grouped according to LBP.
    F1-4
    Fig. 1:
    Linear regression using the Pearson method to assess the correlation between the LBP levels and the disease severity scores.

    The discriminating power of LBP to predict 28-day mortality was tested using the area under a receiver operating characteristic (ROC) curve. The area under ROC curve for LBP was 0.809 [95% CI: 0.691–0.927] (Fig. 2). By analyzing the ROC curve, the cut-off point for LBP to best predict 28-day mortality was obtained (46 ng/mL; sensitivity: 72.7%; specificity: 83.3%).

    F2-4
    Fig. 2:
    Receiver operating characteristic (ROC) curve to test the discriminating power of LBP to predict 28-day mortality. The area under ROC curve for LBP is 0.809 (95% CI: 0.691–0.927).

    The clinical characteristics and outcomes in patient subgroups stratified by LBP level are listed in Table 2. The ICU and 28-day mortality rates for the patients who had a lower LBP were significantly higher than for those with a higher LBP. Follow-up to 28 days or the time of death was complete for the entire groups. The cumulative rates of survival at 28 days were 16.7% and 72.7% for the low-LBP group and high-LBP group, respectively (p < 0.001) (Fig. 3).

    F3-4
    Fig. 3:
    Cumulative survival in patients with high (n = 22) and low (n = 36) LBP after admission to intensive care unit. Day 0 indicates the 1st day of admission to intensive care unit.

    To clarify further whether the association between low levels of LBP and mortality was confounded by liver dysfunction and the severity of multiple organ dysfunction, we tried to compare the concentrations of LBP between the 28-day survivors and non-survivors with comparable Child-Pugh, MELD, and SOFA scores. We used the median values as cut-off values to stratify the patients into high and low groups of different prognostic scores. The differences in the levels of LBP between survivors and non-survivors remained, while the differences in Child-Pugh scores between survivors and non-survivors had been eliminated (Table 3), suggesting that LBP level was associated with mortality independent of liver dysfunction. However, the differences in the levels of LBP between survivors and non-survivors did not consistently remain when we stratified patients using MELD and SOFA scores (Supplementary Tables 1 and 2).

    T3-4
    Table 3:
    Lipopolysaccharide-binding protein and outcome data in patient subgroups stratified by Child-Pugh scores.

    4. Discussion

    This study is the first to evaluate the relationship between levels of serum LBP and outcomes in critically ill cirrhotic patients with severe sepsis. This investigation showed that low levels of LBP at admission to ICU are associated with impaired liver reserve, multiple organ dysfunction and increased mortality in this clinical setting.

    Bacterial translocation and episodic endotoxemia are common phenomena in cirrhotic patients.35,36 Although LBP has served as a surrogate marker of bacterial translocation in liver cirrhosis,2,15 its clinical value in the setting of sepsis remains inconclusive. Data about the association between LBP concentrations at admission to the ICU and outcomes have been conflicting. In this study, we found that 28-day mortality rates were significantly higher in patients with lower levels of LBP at admission to ICU. This finding is in agreement with previous studies,13,37 but in contrast to others, in which high levels of LBP were either associated with adverse outcomes38,39 or not related to outcomes.21,40 Despite the conflicting data about the prognostic significance of LBP in the literature, the dynamics of LBP levels during sepsis were consistent. The higher levels were observed at the initial tests and decreased thereafter, with the lowest at the last tests.21,37,40 The reasons for this dynamic trend are not clear. Although Prucha et al reported that liver failure was not likely to be responsible for this phenomenon in a study of small sample size,21 their conclusion should not readily be extrapolated to cirrhotic patients, in whom acute or chronic liver failure may occur in the setting of severe sepsis and may impact the biosynthesis of LBP.

    Investigators have reported dual biological activity of LBP, namely both pro- and anti-inflammatory properties.18 In contrast to the upregulation of the LPS-induced cytokine release by LBP, an LPS-neutralizing effect has also been observed at high concentrations of LBP. LBP could suppress endotoxin-triggered cytokine secretion and prevent liver failure, leading to a significantly increased survival rate in endotoxin-challenged mice as well as in a murine model of bacteremia.19 However, Zweigner et al investigated whether high levels of acute-phase concentrations of LBP in patients with severe sepsis could modulate the LPS-induced TNF-α secretion from monocytes.41 They found that serum containing high concentrations of LBP from septic patients could reduce TNF-α overproduction, an effect that was reversed by LBP depletion. In agreement of this contention, our results showed that TNF-α levels were significantly lower in the high LBP group.

    Interestingly, in patients with sequential episodes of sepsis, LBP response seems to be of lesser magnitude following each consecutive episode of sepsis.37 This phenomenon may substantiate the prognostic significance of LBP in cirrhotic patients with severe sepsis, in whom low levels of LBP may reflect both impaired hepatic synthesis and accumulating adverse effects of sequential sepsis episodes in susceptible individuals.

    The mechanisms behind how LBP prevents endotoxin-induced toxicity remain unclear. It has been shown that LBP in vivo is associated with HDL.17 Moreover, LBP facilitates transfer of LPS into HDL, resulting in a detoxification process.17,42,43 In this regard, our group has shown that serum levels of HDL are inversely correlated with liver reserve, disease severity, and levels of inflammatory cytokines in cirrhotic patients with severe sepsis.12 Taken together, impaired synthesis of HDL and LBP from diseased livers may make cirrhotic patients even more susceptible to the toxicity of bacterial products. High levels of endotoxin during sepsis may further overwhelm the already impaired neutralization ability provided by low levels of HDL and LBP and subsequently become even more unopposed, thus perpetuating the overproduction of inflammatory cytokines. A vicious cycle ensues, with further failure of multiple organ functions.

    In contrast to subgroup analysis stratified by the Child-Pugh score, the differences in the levels of LBP between survivors and non-survivors did not consistently remain in the sub-group analysis stratified by MELD and SOFA scores (Supplementary Tables 1 and 2). Because both MELD and SOFA scores evaluate extra-hepatic organ function in addition to hepatic function, our findings suggested the significant confounding effects of extra-hepatic dysfunction on the association between LBP and outcomes. In this regard, LBP may impact survival through its pathophysiological link with multiple organ failure. Further studies are needed to clarify this issue.

    There are limitations in our study. First, we only measured LBP levels at admission to ICU. As previously discussed, the concentrations of LBP levels may vary significantly over the course of a given septic episode.21,37,40 Secondly, our study suffers from absence of a non-cirrhotic control group. Therefore, the impact of pre-existing chronic liver failure on LBP levels cannot be elucidated. Finally, the case number is small. We need a bigger cohort to allow better sub-group analyses to evaluate the confounding effects of disease scores on the association between LBP levels and mortality.

    In conclusion, low serum levels of LBP are associated with increased concentrations of TNF-α and adverse outcomes of cirrhotic patients with severe sepsis. These findings may shed light on the pathophysiology in cirrhosis with severe sepsis. Whether the levels of LBP can enable clinicians to identify those patients who are at risk for deterioration and in need of timely intervention is unknown. It is also unknown whether recombinant LBP can serve as an adjuvant therapeutic strategy in cirrhosis with endotoxemia.44 For potential clinical application of LBP, further investigations on the best timing of the testing and dosing regimen in order to achieve a protective effect of LBP are needed.

    Acknowledgments

    This work was partially supported by grants from the Chang Gung Medical Research Fund CMRPG3A1091, Chang Gung Memorial Hospital, Taipei, Taiwan, R.O.C.

    References

    1. Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis. 2008;28:26-42.
    2. Wiest R, Garcia-Tsao G. Bacterial translocation in liver cirrhosis. Hepatology. 2005;41:422-433.
    3. Wiest R, Cadelina G, Milstien S, McCuskey RS, Garcia-Tsao G, Groszmann RJ. Bacterial translocation up-regulates GTP-cyclohydrolase I in mesenteric vasculature of cirrhotic rats. Hepatology. 2003;38:1508-1515.
    4. Wiest R, Das S, Cadelina G, Garcia-Tsao G, Milstien S, Groszmann RJ. Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility. J Clin Invest. 1999;104:1223-1233.
    5. Ulevitch RJ, Tobias PS. Recognition of gram-negative bacteria and endotoxin by the innate immune system. Curr Opin Immunol. 1999;11:19-22.
    6. Triantafilou M, Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol. 2002;23:301-304.
    7. Pérez del Pulgar S, Pizcueta P, Engel P, Bosch J. Enhanced monocyte activation and hepatotoxicity in response to endotoxin in portal hypertension. J Hepatol. 2000;32:25-31.
    8. Albillos A, Hera Ad Ade L, Reyes E, Monserrat J, Muñoz L, Nieto M, et al. Tumour necrosis factor-alpha expression by activated monocytes and altered T-cell homeostasis in ascitic alcoholic cirrhosis: amelioration with norfloxacin. J Hepatol. 2004;40:624-631.
    9. Tazi KA, Quioc JJ, Saada V, Bezeaud A, Lebrec D, Moreau R. Upregulation of TNF-alpha production signaling pathways in monocytes from patients with advanced cirrhosis: possible role of Akt and IRAK-M. J Hepatol. 2006;45:280-289.
    10. Hsieh HG, Huang HC, Lee FY, Chan CY, Lee JY, Lee SD. Kinetics of cytokine expression in cirrhotic rats. J Chin Med Assoc. 2011;74:385-393.
    11. Tsai MH, Peng YS, Chen YC, Liu NJ, Ho YP, Fang JT, et al. Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock. Hepatology. 2006;43:673-681.
    12. Tsai MH, Peng YS, Chen YC, Lien JM, Tian YC, Fang JT, et al. Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis. J Hepatol. 2009;50:906-915.
    13. Opal SM, Scannon PJ, Vincent JL, White M, Carroll SF, Palardy JE, et al. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. J Infect Dis. 1999;180:1584-1589.
    14. Schumann RR, Latz E. Lipopolysaccharide-binding protein. Chem Immunol. 2000;74:42-60.
    15. Albillos A, de la Hera A, Gonzalez M, Moya JL, Calleja JL, Monserrat J, et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology. 2003;37:208-217.
    16. Arditi M, Zhou J, Dorio R, Rong GW, Goyert SM, Kim KS. Endotoxin-mediated endothelial cell injury and activation: role of soluble CD14. Infect Immun. 1993;61:3149-3156.
    17. Wurfel MM, Kunitake ST, Lichenstein H, Kane JP, Wright SD. Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med. 1994;180:1025-1035.
    18. Gutsmann T, Müller M, Carroll SF, MacKenzie RC, Wiese A, Seydel U. Dual role of lipopolysaccharide (LPS)-binding protein in neutralization of LPS and enhancement of LPS-induced activation of mononuclear cells. Infect Immun. 2001;69:6942-6950.
    19. Lamping N, Dettmer R, Schroeder NW, Pfeil D, Hallatschek W, Burger R, et al. LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. J Clin Invest. 1998;101:2065-2071.
    20. Myc A, Buck J, Gonin J, Reynolds B, Hammerling U, Emanuel D. The level of lipopolysaccharide-binding protein is significantly increased in patients with the systemic inflammatory response syndrome. Clin Diagn Lab Immunol. 1997;4:113-116.
    21. Prucha M, Herold I, Zazula R, Dubska L, Dostal M, Hildebrand T, et al. Significance of lipopolysaccharide-binding protein (an acute phase protein) in monitoring critically ill patients. Crit Care. 2003;7:R154-R159.
    22. Schumann RR, Kirschning CJ, Unbehaun A, Aberle HP, Knope HP, Lamping N, et al. Lipopolysaccharide binding protein (LBP) is a secretory class 1 acute phase protein requiring binding of the transcription factor STAT-3, C/EBPβ, and AP-1. Mol Cell Biol. 1996;16:3490-3503.
    23. Ginès P, Fernández J, Durand F, Saliba F. Management of critically-ill cirrhotic patients. J Hepatol. 2012;56(Suppl 1):S13-S24.
    24. Jalan R, Gines P, Olson JC, Mookerjee RP, Moreau R, Garcia-Tsao G, et al. Acute-on chronic liver failure. J Hepatol. 2012;57:1336-1348.
    25. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1644-1655.
    26. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858-873.
    27. Tsai MH, Chen YC, Yang CW, Jenq CC, Fang JT, Lien JM, et al. Acute renal failure in cirrhotic patients with severe sepsis: value of urinary interleukin-18. J Gastroenterol Hepatol. 2013;28:135-141.
    28. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus in the bleeding esophageal varices. Br J Surg. 1973;60:648-652.
    29. Kamath PS, Weisner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33:464-470.
    30. Wehler M, Kokoska J, Reulbach U, Hahn EG, Strauss R. Short-term prognosis in critically ill patients with cirrhosis assessed by prognostic scoring systems. Hepatology. 2001;34:255-261.
    31. Tsai MH, Chen YC, Ho YP, Fang JT, Lien JM, Chiu CT, et al. Organ system failure scoring system can predict hospital mortality in critically ill cirrhotic patients. J Clin Gastroenterol. 2003;37:251-257.
    32. Tsai MH, Peng YS, Lien JM, Weng HH, Ho YP, Yang C, et al. Multiple organ system failure in critically ill cirrhotic patients. Digestion. 2004;69:190-200.
    33. Hanley J, McNeil B. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143:29-36.
    34. Youden WJ. Index for rating diagnosis tests. Cancer. 1950;3:32-35.
    35. Cirera I, Bauer TM, Navasa M, Vila J, Grande L, Taurá P, et al. Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol. 2001;34:32-37.
    36. Lin RS, Lee FY, Lee SD, Tsai YT, Lin HC, Lu RH, et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J Hepatol. 1995;22:165-172.
    37. Blairon L, Wittebole X, Laterre PF. Lipopolysaccharide binding protein serum levels in patients with severe sepsis due to gram-positive and fungal infections. J Infect Dis. 2003;187:287-291.
    38. Carroll SF, Dedrick L, White ML. Plasma levels of lipopolysaccharide binding protein (LBP) correlate with outcome in sepsis and other patients. Abstracts of the Sixth Vienna Shock Forum. 1997, Abstract 101.
    39. Schumann RR, Zweigner J, Lamping N, Gramm HJ. Significantly elevated levels of lipopolysaccharide binding protein (LBP) in patients with severe sepsis: a prospective cohort study with 109 surgical ICU patients. In: Program and abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1996. Abstract LB17.
    40. Villar J, Pérez-Méndez L, Espinosa E, Flores C, Blanco J, Muriel A, et al. Serum lipopolysaccharide binding protein levels predict severity of lung injury and mortality in patients with severe sepsis. PLoS One. 2009;4:e6818.
    41. Zweigner J, Gramm HJ, Singer OC, Wegscheider K, Schumann RR. High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes. Blood. 2001;98:3800-3808.
    42. Levine DM, Parker TS, Donnelly TM, Walsh A, Rubin AL. In vivo protection against endotoxin by plasma high density lipoprotein. Proc Natl Acad Sci U S A. 1993;90:12040-12044.
    43. Pajkrt D, Doran JE, Koster F, Lerch PG, Arnet B, van der Poll T, et al. Anti-inflammatory effects of reconstituted high-density lipoprotein during human endotoxemia. J Exp Med. 1996;184:1601-1608.
    44. Cotroneo TM, Nemzek-Hamlin JA, Bayliss J, Su GL. Lipopolysaccharide binding protein inhibitory peptide alters hepatic inflammatory response post-hemorrhagic shock. Innate Immun. 2012;18:866-875.

    Appendix A. Supplementary data

    Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jcma.2013.10.006.

    FAU1-4
    Figure
    Keywords:

    lipopolysaccharide binding protein; liver cirrhosis; severe sepsis

    © 2014 by Lippincott Williams & Wilkins, Inc.