ObjectiveThis study was performed to investigate gut-derived bacterial translocation and the time course of endotoxin (lipopolysaccharide [LPS]) and tumor necrosis factor (TNF) appearance, both in portal and systemic circulation. Summary Background DataThe significance of intestinal bacteria/endotoxin translocation or TNF formation in the development of systemic sepsis has been disputed. MethodsA rat model of hemorrhagic shock (30-35 mm Hg for 90 min) and resuscitation was used. ResultsBacterial translocation was histologically observed in the small intestinal wall 30 minutes after resuscitation. A significant increase in LPS concentrations was found in the portal vein (91.7 ± 30.6 pg/mL) at 90 minutes, which remained steady until 150 minutes after shock. Lipopolysaccharide increased in the systemic circulation, the levels became significant at 120 minutes, and peaked (66.5 ± 39.2 pg/mL) 150 minutes after shock. Tumor necrosis factor concentrations were found to be significantly elevated in both portal and systemic circulation (75.6 ± 22.1 vs. 58.4 ± 14.1 pg/mL) at 90 minutes post-shock. Although there was no further increase in TNF concentration in the portal blood, TNF peaked (83.5 ± 17.7 pg/mL) in systemic circulation at 120 minutes and still was markedly increased at 150 minutes post-shock. In addition, higher LPS and TNF concentrations in systemic circulation were found in the nonsurvivors than in the surviving animals at the end of resuscitation. ConclusionsThese results suggest that hemorrhagic shock may lead to early bacterial translocation in the intestinal wall and transient access of gut-derived LPS and LPS-induced mediators into the circulation predominantly via the portal circulation. 100

ObjectiveThis study was conducted to determine the role of gut-derived bacteria/endotoxin in the pathogenesis of the multiple-organ damage and mortality, the possible beneficial effect of recombinant bactericidal/permeability-increasing protein (rBPI21), and whether neutralizing endotoxemia by rBPI21 treatment influences tumor necrosis factor (TNF) formation in rats after hemorrhagic shock and resuscitation. Summary Background DataHypovolemic shock might be associated with bacterial or endotoxin translocation as well as systemic sepsis. Similar to bactericidal/permeability-increasing (BPI) protein, rBPI21 has been found to bind endotoxin and inhibit TNF production. MethodsA rat model of prolonged hemorrhagic shock (30 to 35 mm Hg for 180 min) followed by adequate resuscitation was employed. Recombinant bactericidal/permeability-increasing protein was administered at 5 mg/kg intravenously. The control group was treated similarly to the BPI group, but received thaumatin as a protein-control preparation in the same dose as rBPI21. ResultsImmediately after resuscitation (230 min), plasma endotoxin levels in the control group (61.0 + 16.3 pg/mL) were almost neutralized by rBPI21 treatment (13.8 ± 4.8 pg/mL, p < 0.05). Plasma TNF levels were not significantly influenced by rBPI21 treatment. The 48-hour survival rate was 68.8% in the treatment group versus 37.5% in the control group (p = 0.08). Microscopic histopathologic examination revealed relatively minor damage to various organs in the treatment group. ConclusionsThese data suggest that hemorrhagic shock may lead to bacterial/endotoxin translocation with concomitant TNF formation, endogenous endotoxemia may play an important role in the pathogenesis of multiple-organ failure after shock and trauma, TNF formation at an early stage 398

These data suggest that a) endotoxin derived from enteric bacteria might play an important role in the pathogenesis of lung injury; and b) antiendotoxin agents, such as WN1 222-5, appear to protect against endogenous bacterial endotoxin-related disorders in severe hemorrhagic shock in rats.