Enhanced monocyte activation and hepatotoxicity in response to endotoxin in portal hypertension

Pulgar, S. Perez del; Pizcueta, Pilar; Engel, Pablo; Bosch, Jaume

doi:10.1016/s0168-8278(00)80185-3

Cited by 30 publications

(10 citation statements)

References 28 publications

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“…Thus, we believe that activated monocytes and liver-resident macrophages are the major source of circulating suPAR in patients with cirrhosis, even in the absence of overt infection and SIRS. We and others [27,45,46] have previously shown activation of circulating and hepatic monocytes with progressive fibrosis, cirrhosis, and portal hypertension, and our current data have demonstrated a correlation between serum suPAR with serum IL-10, which is mainly derived from monocyte progeny [47]. Furthermore, endotoxaemia and bacterial translocation are characteristic of decompensated cirrhosis, thus providing a source of TLR agonists in patients with advanced cirrhosis independent of overt infection [28,30,48].…”

Section: Discussionsupporting

confidence: 68%

Soluble urokinase plasminogen activator receptor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short‐term mortality

et al. 2013

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Objective. Patients with decompensated cirrhosis are susceptible to bacterial infections, which are associated with organ failure and a high mortality rate. Reliable biomarkers are needed to identify patients who require intensified treatment. Our objective was to study the regulation and prognostic relevance of elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) in patients with advanced cirrhosis.Design, setting and participants. We examined the associations between serum and ascitic fluid (AF) suPAR and liver function, bacterial infection, and shortterm mortality in 162 consecutive patients with decompensated cirrhosis undergoing diagnostic paracentesis in a tertiary health care centre in Germany.Main outcome measure. Twenty-eight-day mortality.Results. Circulating suPAR levels were increased in patients with decompensated cirrhosis and correlated with the severity of liver dysfunction and systemic inflammation but were not indicative of bacterial infection. Circulating suPAR levels >14.4 ng mL À1 predicted 28-day mortality, even after adjustment for liver function and confounders [HR = 3.05 (1.35-6.90); P = 0.0076] equal to the MELD score (AUC = 0.71; 95% CI = 0.61-0.81; P < 0.001). Cut-off levels derived from cohorts without liver disease were not applicable due to the low specificity. AF suPAR levels were elevated during spontaneous bacterial peritonitis (SBP), but not during episodes in which bacteria or bacterial DNA was translocated into the ascites. AF suPAR levels correlated poorly with systemic suPAR but were associated with a more severe course of SBP and a worse outcome. In vitro experiments revealed that monocytes, and to a lesser extent neutrophils, secrete suPAR after Toll-like-receptor ligation, which led to rapid urokinase plasminogen activator receptor cleavage followed by increased synthesis.Conclusion. Blood and ascitic suPAR levels provide distinct, but relevant prognostic information on the severity of complications in patients with end-stage liver disease.

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Section: Discussionsupporting

confidence: 68%

Soluble urokinase plasminogen activator receptor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short‐term mortality

et al. 2013

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“…In this context, the importance of bacterial translocation and endotoxemia cannot be over-emphasized. In fact, it has been shown that in liver cirrhosis, endotoxemia can lead to exaggerated cytokine production, over-expression of nitric oxide synthase and hemodynamic impairment [3,5]. Therefore, it is attractive to find new therapeutic options to modulate the cascade of inflammatory response trig- Recently, the capability of lipoprotein to bind and neutralize bacterial products has drawn more and more attention.…”

Section: Discussionmentioning

confidence: 99%

“…In response to endotoxin challenge, cirrhotic patients exhibit an augmented capacity to produce pro-inflammatory cytokines [5][6][7], which may be linked to multiple organ dysfunction in severe sepsis. Despite the advance in intensive care, the prognosis of severe sepsis is still grave [8].…”

Section: Introductionmentioning

confidence: 99%

Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis

Tsai

Peng

Chen

et al. 2009

Journal of Hepatology

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“…4 5 Endotoxaemia resulting from bacterial translocation may adversely affect liver function and may contribute to the systemic haemodynamic derangement of liver cirrhosis. 6 Therefore, restoring the integrity of the intestinal barrier is an important goal in the management of liver cirrhosis.…”

mentioning

confidence: 99%

Insulin-like growth factor I improves intestinal barrier function in cirrhotic rats

Lorenzo-Zúñiga

Rodríguez‐Ortigosa²,

Bartolı́³

et al. 2006

Gut

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Background and aims: In liver cirrhosis, disruption of the intestinal barrier facilitates bacterial translocation and spontaneous bacterial peritonitis. Insulin-like growth factor I (IGF-I) is an anabolic hormone synthesised by hepatocytes that displays hepatoprotective activities and trophic effects on the intestine. The aim of this study was to investigate the effect of IGF-I on intestinal barrier function in cirrhotic rats. Methods: In rats with carbon tetrachloride induced cirrhosis, we investigated the effect of IGF-I therapy on: (a) portal pressure; (b) intestinal histology and permeability to endotoxin and bacteria; (c) intestinal expression of cyclooxygenase 2 (COX-2) and tumour necrosis factor a (TNF-a), two factors that influence in a positive and negative manner, respectively, the integrity of the intestinal barrier; (d) intestinal permeability to 3 H-mannitol in rats with bile duct ligation (BDL); and (e) transepithelial electrical resistance (TER) of polarised monolayers of rat small intestine epithelial cells. Results: IGF-I therapy reduced liver collagen expression and portal pressure in cirrhotic rats, induced improvement in intestinal histology, and caused a reduction in bacterial translocation and endotoxaemia. These changes were associated with diminished TNF-a expression and elevated COX-2 levels in the intestine. IGF-I reduced intestinal permeability in BDL rats and enhanced barrier function of the monolayers of epithelial intestinal cells where lipopolysaccharide (LPS) caused a decrease in TER that was reversed by IGF-I. This effect of IGF-I was associated with upregulation of COX-2 in LPS treated enterocytes. Conclusions: IGF-I enhances intestinal barrier function and reduces endotoxaemia and bacterial translocation in cirrhotic rats. IGF-I therapy might be useful in the prevention of spontaneous bacterial peritonitis in liver cirrhosis.

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Enhanced monocyte activation and hepatotoxicity in response to endotoxin in portal hypertension

Cited by 30 publications

References 28 publications

Soluble urokinase plasminogen activator receptor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short‐term mortality

Soluble urokinase plasminogen activator receptor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short‐term mortality

Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis

Insulin-like growth factor I improves intestinal barrier function in cirrhotic rats

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