Hepatic failure and coma following liver resection is reversed by manipulation of gut contents: the role of endotoxin

Leeuwen, Paul A. M. van; Hong, Rutao; Rounds, Jan D.; Wilmore, Douglas W.; Wesdorp, R. I. C.

doi:10.1016/0261-5614(91)90171-8

Cited by 37 publications

(22 citation statements)

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“…We found that circulating endotoxin levels were significantly increased in patients with cirrhosis of both alcohol-induced and other etiologies except in the subgroup of Child-Pugh class B and C patients treated with lactulose, an agent known to reduce the intestinal content of endotoxin-containing Gram-negative gut flora. 32 Conversely, treatment with lactulose did not significantly influence any other study parameter. Consequently, lactulose-treated patients were included in this report to allow comparison of study parameters in subgroups with varying plasma endotoxin profiles and thereby obtain additional insight into the relative influences of endotoxin and other microbial stimuli on circulating TNF-␣ and sTNFR levels in cirrhosis.…”

Section: Discussionmentioning

confidence: 88%

“…Eight patients were receiving treatment for hepatic encephalopathy with lactulose (4-O-␤-d-galactopyranosyl-d-fructose; Solvay Pharmaceuticals, Sydney, Australia), which is of relevance because this nonabsorbable disaccharide reduces the intestinal content of endotoxin-containing Gram-negative gut flora. 32 Patients were considered to have alcohol-related cirrhosis if alcohol intake had been in excess of 80 g/day in men and 30 g/day in women for more than 5 years and if testing for viral, metabolic, and immune etiologies was negative. 17 Only patients who had been abstinent from alcohol for at least 3 months were included, because alcohol influences the sensitivity of macrophages to endotoxin and the production of TNF-␣ by PBMCs.…”

Section: Methodsmentioning

confidence: 99%

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Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis

et al. 2003

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Activation of macrophages by endotoxin is assumed responsible for increased circulating tumor necrosis factor ␣ (TNF-␣) and soluble TNF receptor (sTNFR) levels in cirrhosis. Relevant to this is expression of Toll-like receptor (TLR) 4 and TLR2, which is critically involved in production of TNF-␣ in response to endotoxin and Gram-positive microbial stimuli, respectively. The first studies on this in cirrhosis are reported here. In 36 cirrhotic patients and 32 controls, we measured (1) circulating endotoxin, TNF-␣, and sTNFR levels; (2) peripheral blood mononuclear cell (PBMC) expression of TLR4 and TLR2, and (3) in vitro TNF-␣ production by PBMCs stimulated with endotoxin or Staphylococcus aureus enterotoxin B (SEB). PBMC expression of TLR2, circulating TNF-␣ levels, and in vitro TNF-␣ production were reassessed after supplementation with a synbiotic regimen known to increase intestinal levels of Gram-positive bacteria. Endotoxin, TNF-␣, and sTNFR levels were significantly increased in cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2 but not TLR4 was significantly up-regulated in cirrhosis and correlated significantly with serum TNF-␣ and sTNFR levels. In vitro TNF-␣ production by PBMCs stimulated by SEB was significantly blunted. Supplementation with the synbiotic regimen resulted in significant up-regulation of PBMC expression of TLR2. Serum TNF-␣ levels were further increased and in vitro TNF-␣ production further reduced in most patients. In conclusion, up-regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies, contrary to previous assumptions, an important stimulatory role for Gram-positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF-␣ and sTNFR levels in cirrhosis.

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Section: Discussionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis

et al. 2003

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“…Also, the presence of RES depression has been reported in various liver injury models. 39,40 In the present study, RES depression may also be another factor that contributes for BT development.…”

Section: Groups Necrosis Inflammationmentioning

confidence: 50%

Effects of Lycium barbarum on bacterial translocation in thioacetamide-induced liver injury in rats

et al. 2015

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Background and study aim: The aim of the present study was to investigate the effects of Lycium barbarum (LB) on bacterial translocation (BT) frequency in thioacetamide (TAA)-induced liver injury in rats. Materials and methods: Group 1 was the control. In group 2 (TAA), rats received TAA daily for 3 days. In group 3 (TAA+LB), Lycium barbarum was administered orally 25 mg/kg for 21 days prior to the first TAA injection. In group 4 (LB), rats received only Lycium barbarum. Results: In our study, Lycium barbarum treatment did not attenuate liver damage. Lycium barbarum treatment decreased ileal E. coli counts and intestinal damage but it did not alter BT frequency. Conclusions: In conclusion, the effects of Lycium barbarum on BT may be related to ongoing severe liver damage in this model.

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“…[60][61][62][63] After major liver resection, however, the number of Kupffer cells is strongly reduced, resulting in the spillover of gut-derived endotoxin into the systemic circulation. [64][65][66] Endotoxin exerts its biological effects by activating such immune cells as monocytes and macro-phages. After exposure to endotoxin, these cells readily produce and release several inflammatory mediators, such as TNF-␣ and IL-1, thereby inducing a systemic inflammatory response.…”

Section: Bpi In Liver Surgerymentioning

confidence: 99%

“…Furthermore, in contrast to a high mortality rate in the control group, no deaths occurred in the treated animals. 66 Evaluation of ex vivo immune functions in a similar animal model showed that major liver resection resulted in a severe immunosuppression, identified by the decreased proliferative response of splenic B and T lymphocytes, together with reduced LPS-stimulated production of TNF and IL-6 by splenocytes. 89 The preservation of these immune functions by binding intestinal endotoxin with cholestyramine further substantiated that translocation of gut-derived endotoxins is of major importance in the pathogenesis of complications after partial hepatectomy.…”

Section: Bpi In Liver Surgerymentioning

confidence: 99%

Potential applications of N-terminal recombinant fragments of bactericidal/permeability-increasing protein in liver surgery

et al. 1999

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Bactericidal/permeability-increasing protein (BPI) was first isolated by Elsbach and Weiss in 1978. 1,2 It is a natural host-defense protein of 55 kd found in the azurophilic granules of human neutrophils, which are important in the host defense against infections. The protein was named after one of its first discovered properties, the potential to kill bacteria by increasing the permeability of their cell walls. 1,2 This ability to kill bacteria has led to further studies of the functions of BPI, from which researchers have discovered several potentially useful properties. In this article, we first give a brief review of the most important in vitro and in vivo studies showing the functions and properties of BPI and then focus on the potential applications of one of the more stable recombinant BPIs, rBPI 21 , in the field of liver surgery and transplantation. The Main Effects of BPI Antibacterial ActionBPI shows antimicrobial activity against a wide range of gram-negative bacteria. 1-3 The cell envelope of gram-negative bacteria consists of the cytoplasmic membrane, peptidoglycan layer, and an additional barrier, the outer membrane, which is strictly asymmetric with respect to its lipid composition. The outer leaflet of this membrane is composed mainly of lipopolysaccharides (LPS; endotoxins). LPS consists of an oligosaccharide or polysaccharide and a covalently linked glycolipid component (lipid A) that anchors the LPS in the outer membrane. 4 The selectivity of BPI against gram-negative bacteria has been attributed to the strong attraction of BPI for this LPS in the bacterial envelope, especially the high affinity for its lipid A component. 5,6 It has become evident that the LPS structure primarily determines bacterial sensitivity. Strains bearing LPS with short polysaccharide chains in their outer membrane are the most sensitive. Long polysaccharide chains sterically hinder the access of BPI to the binding sites in the inner core and the lipid A regions of LPS, thereby reducing the affinity of BPI for the envelope LPS, necessitating higher ambient BPI concentrations to achieve the required amount of bound BPI to produce its biological effects. 3,6,7 The cytotoxic effect of BPI on gram-negative bacteria can be divided into two stages. When BPI binds to the outer membrane, several immediate effects are manifest, including arrest of bacterial growth, discrete changes in the permeability of the outer membrane, and selective activation of several envelope enzymes, which degrade phospholipids and peptidoglycans. These changes are evident despite preservation of the functional integrity of the biochemical machinery in the nongrowing bacteria. In fact, certain manipulations result in repair of the envelope alterations and resumption of growth, therefore indicating that the initial effects of BPI are not directly bactericidal. 2,8 However, when this process is continued, alterations of the cytoplasmic membrane are produced, resulting in an impairment of the energy metabolism that leads to an irreversible growth arre...

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Hepatic failure and coma following liver resection is reversed by manipulation of gut contents: the role of endotoxin

Cited by 37 publications

References 0 publications

Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis

Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis

Effects of Lycium barbarum on bacterial translocation in thioacetamide-induced liver injury in rats

Potential applications of N-terminal recombinant fragments of bactericidal/permeability-increasing protein in liver surgery

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