RESUMO
The mechanism of liver injury in endotoxemia is unclear. Previous studies have shown that splenectomy protects the liver from endotoxin-induced injury. The purpose of this study was to determine the relationship of TNFalpha and IFNgamma release and endotoxin-induced liver injury in splenectomized and nonsplenectomized rats. Splenectomized and nonsplenectomized (Sham) rats with chronic catheters in the aorta and inferior vena cava (IVC) were parenterally infused with 10 to 5000 microg/kg endotoxin. TNFalpha, IFNgamma, and alanine aminotransferase (ALT), a marker of hepatocellular damage, were measured in aortic blood. Compared to sham controls, splenectomized animals demonstrated significantly reduced endotoxin-induced ALT concentrations at endotoxin doses >10 microg/kg. Peak endotoxin-induced TNFalpha concentrations were not significantly different between the splenectomized and sham groups. In contrast, peak endotoxin-induced IFNgamma concentrations were significantly decreased in the splenectomized group. These data suggest a relationship between endotoxin-induced IFNgamma and liver injury. We speculate that the spleen contributes to the endotoxin-induced liver injury by modulating release of IFNgamma.
Assuntos
Endotoxinas/toxicidade , Interferon gama/biossíntese , Fígado/efeitos dos fármacos , Fígado/lesões , Baço/fisiologia , Alanina Transaminase/sangue , Animais , Interferon gama/sangue , Fígado/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Esplenectomia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
We have previously shown that systemic infusion of the bacterial toxins Staphylococcal enterotoxin B (SEB) and endotoxin (LPS) induces hepatic dysfunction as measured by decreased biliary indocyanine green (ICG) excretion. In this study, we compare the effects of these bacterial toxins after infusion into the portal and systemic circulation and directly measure biliary bile acid excretion as a measure of cholestasis. We hypothesized that bacterial toxins infused into the portal vein would induce greater hepatic dysfunction than toxins infused into the systemic circulation. Using a chronically catheterized rat model, biliary bile acid excretion was directly measured after infusion of LPS at 10 and 100 microg/kg with and without 50 microg/kg SEB into the portal vein (IPV) or inferior vena cava (IV) at baseline, and at 6 and 24 h. We found that when LPS was infused alone, only IPV administration caused a significant decrease in bile acid excretion at 6 h. There was no change in bile acid excretion after IV administration of LPS. In contrast, when the combination of LPS and SEB was infused, both IV and IPV administration significantly decreased bile acid excretion at 6 and 24 h. At 6 h post-LPS and -SEB administration, the decrease in bile acid excretion was significantly greater after IPV than IV administration. There was no site-specific difference in IFN-gamma release after infusion of toxins. However, peak TNFalpha release was decreased in IPV-infused rats [10 microg/kg (P < 0.05) or 100 microg/kg (P = ns) LPS with SEB] compared with the same doses in IV-infused rats. These data question the role of systemic TNF-alpha and IFN-gamma in regulating hepatic dysfunction and suggest a differential functional response of the liver to systemic and gut-derived septic events. This study also further explains the frequent development of liver dysfunction in patients with sepsis, multisystem organ failure, and other diseases with altered intestinal permeability.