Immunostimulatory CpG-oligodeoxynucleotides (CpG-ODN) induce early hepatic injury, but provide a late window for protection against endotoxin-mediated liver damage

Slotta, Jan E.; Scheuer, Cláudia; Menger, Michael D.; Vollmar, Brigitte

doi:10.1016/j.jhep.2005.08.014

Cited by 22 publications

(19 citation statements)

References 64 publications

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“…12,13,38 Moreover, experimental studies have demonstrated that short-term exposure to synthetic oligonucleotides containing CpG motifs or fragments of bacterial DNA results in marked deterioration of the hepatic microcirculation. 39 This is likely to occur at sinusoidal and postsinusoidal sites, as suggested by the much lower decrease in hepatic vascular resistance in response to increased liver perfusion in bactDNA(þ) patients as compared with patients with undetectable bacterial DNA fragments.…”

Section: Discussionmentioning

confidence: 99%

Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis

et al. 2010

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Presence of bacterial DNA in noninfected patients with cirrhosis and ascites is associated with a marked inflammatory response including activation of the inducible form of nitric oxide synthase and release of nitric oxide, similar to that observed in patients with spontaneous bacterial peritonitis. Although presence of bacterial DNA is associated with an impaired prognosis, no information is available regarding its hemodynamic consequences. Systemic and hepatic hemodynamics before and after a liquid test meal were assessed in a series of 75 noninfected patients with cirrhosis (55 with ascites). Bacterial DNA was measured by polymerase chain reaction. Bacterial DNA was detected only in patients with ascites. Clinical data and liver function were similar in ascitic patients with presence (n 5 21) or absence of bacterial DNA (n 5 34). Bacterial-DNA(1) patients had significantly lower mean arterial pressure (P 5 0.002) and systemic vascular resistance (P 5 0.03) than bacterial-DNA(2) patients. Cardiac output, cardiopulmonary pressures, hepatic venous pressure gradient (HVPG), and hepatic blood flow were similar in both groups. Thirty minutes after the test meal, in response to increased blood flow caused by postprandial hyperemia, there was a significantly greater increase in HVPG and impaired hepatic vasorelaxation in bacterial-DNA(1) as compared with bacterial-DNA(2) patients, which indicates hepatic endothelial dysfunction. Indeed, the increase in HVPG after the test meal significantly correlated with serum bacterial DNA concentration. Conclusion: Presence of bacterial DNA, a marker of bacterial translocation, is associated with aggravation of peripheral vasodilation and with worsening of intrahepatic endothelial dysfunction. (HEPATOLOGY 2010;52:2044-2052 P ortal hypertension is a serious consequence of cirrhosis that can result in life-threatening complications with increased mortality and morbidity.1 The primary factor in the pathophysiology of portal hypertension is increased intrahepatic resistance to portal-collateral blood flow. Portal hypertension is further aggravated by increased portal venous inflow, caused by splanchnic vasodilation. Moreover, insufficient nitric oxide (NO) availability in the hepatic microcirculation is considered an important factor that contributes to increase the hepatic vascular resistance. Because of this, the cirrhotic liver, unlike the normal liver, cannot vasodilate in response to a volume flow load such as that caused by meals, which results in abrupt postprandial increases in portal pressure, a concept known as intrahepatic endothelial dysfunction. [2][3][4][5]

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Section: Discussionmentioning

confidence: 99%

Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis

et al. 2010

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“…Sepsis was induced by intraperitoneal administration of endotoxin (dissolved in 0.9% saline solution in a dose of 5 mg/kg body weight). The dose of endotoxin was determined according to the Slota's study [35] and our preliminary experiments. This dose caused a marked increase in protein breakdown but was not lethal.…”

Section: Experimental Designmentioning

confidence: 99%

Effects of β-hydroxy-β-methylbutyrate treatment in different types of skeletal muscle of intact and septic rats

et al. 2010

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β-Hydroxy-β-methylbutyrate (HMB) is a leucine metabolite that may have a positive effect in protein catabolic conditions. Therefore, we hypothesized that HMB treatment could attenuate the sepsis-induced protein catabolic state. The aims of our study were to elucidate the effect of HMB in healthy and septic animals and to evaluate the differences in the action of HMB in different muscle types. Intact and septic (5 mg endotoxin/kg i.p.) rats were administered with HMB (0.5 g/kg/day) or saline. After 24 h, extensor digitorum longus (EDL) and soleus (SOL) muscles were isolated and used for determination of total and myofibrillar proteolysis, protein synthesis, leucine oxidation, activity of cathepsins B and L, chymotrypsin-like activity, and expression of α-subunits of proteasome. Our results indicate that the catabolic state induced by the endotoxin treatment was caused both by increase in protein breakdown (due to activation of proteasome system) and by attenuation of protein synthesis. The EDL (muscle composed of white, fast-twitch fibers) was more susceptible to these changes than the SOL (muscle composed of red, slow-twitch fibers). The HMB treatment had no effect in healthy animals but counteracted the changes in septic animals. The action of HMB was mediated by attenuation of proteasome activity and protein breakdown, not by stimulation of protein synthesis. More pronounced effect of the HMB treatment on myofibrillar proteolysis was observed in the SOL.

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“…Recently, evidence has accumulated showing the significance of TRAF6 in various inflammatory processes, such as lung injury (Cho et al 2005), H. pylori infection-induced gastric diseases (Hirata et al 2006), and hepatic inflammation (Slotta et al 2006). Most of the above-mentioned studies showed that TRAF6 expression was up-regulated in various tissues, implying its pro-inflammatory function.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Tumor Necrosis Factor-Associated Factor 6 Is Associated with Progression of Acute Pancreatitis Complicating Lung Injury in Mice

Zhou

Ding

et al. 2009

Tohoku J. Exp. Med.

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Immunostimulatory CpG-oligodeoxynucleotides (CpG-ODN) induce early hepatic injury, but provide a late window for protection against endotoxin-mediated liver damage

Cited by 22 publications

References 64 publications

Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis

Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis

Effects of β-hydroxy-β-methylbutyrate treatment in different types of skeletal muscle of intact and septic rats

Down-Regulation of Tumor Necrosis Factor-Associated Factor 6 Is Associated with Progression of Acute Pancreatitis Complicating Lung Injury in Mice

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