Hepatic encephalopathy (HE) is a major complication that is closely related to the progression of end-stage liver disease. Metabolic changes in advanced liver failure can promote cognition impairment, attention deficits and motor dysfunction that may result in coma and death. HE can be subdivided according to the type of hepatic injury, namely, type A, which results from acute liver failure, type B, which is associated with a portosystemic shunting without intrinsic liver disease, and type C, which is due to chronic liver disease. Several studies have investigated the pathogenesis of the disease, and most of the mechanisms have been explored using animal models. This article aimed to review the use of preclinical models to investigate HE. The most used animal species are rats and mice. Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications, whereas models of types B and C HE are generally surgically induced lesions in liver tissue, which evolve to hepatic cirrhosis. Preclinical models have allowed the comprehension of the pathways related to HE.

Pulmonary complications are common in acute liver failure (ALF). The role of the lungs in the uptake of harmful soluble endogenous macromolecules was evaluated in a porcine model of ALF induced by hepatic devascularization (n = 8) vs. controls (n = 8). In additional experiments, pulmonary uptake was investigated in healthy pigs. Fluorochrome-labeled modified albumin (MA) was applied to investigate the cellular uptake.

As compared to controls, the ALF group displayed a 4-fold net increased lung uptake of hyaluronan, and 5-fold net increased uptake of both tissue plasminogen activator and lysosomal enzymes. Anatomical distribution experiments in healthy animals revealed that radiolabeled MA uptake (taken up by the same receptor as hyaluronan) was 53% by the liver, and 24% by the lungs. The lung uptake of LPS was 14% whereas 60% remained in the blood. Both fluorescence and electron microscopy revealed initial uptake of MA by pulmonary endothelial cells (PECs) with later translocation to pulmonary intravascular macrophages (PIMs). Moreover, the presence of PIMs was evident 10 min after injection. Systemic inflammatory markers such as leukopenia and increased serum TNF-α levels were evident after 20 min in the MA and LPS groups.

Significant lung uptake of harmful soluble macromolecules compensated for the defect liver scavenger function in the ALF-group. Infusion of MA induced increased TNF-α serum levels and leukopenia, similar to the effect of the known inflammatory mediator LPS. These observations suggest a potential mechanism that may contribute to lung damage secondary to liver disease.

Following hepatic resection, liver regeneration has been associated with concurrent splenic hypertrophy. The mechanisms of this phenomenon are unknown, may be multiple and include: splanchnic sequestration caused by a reduction in the hepatic mass; hepatic growth factors that may indirectly act on the spleen, and the redistribution of the total reticuloendothelial system.

Seventy-five patients (40 males; median age: 60 years) who underwent minor (16%) or major (84%) hepatectomy between September 2004 and October 2009 were included. Prospective measurements of liver and spleen volumes were obtained preoperatively and postoperatively 1 month after hepatectomy using computed tomography (CT). The future remnant liver volume (RLV) was calculated on preoperative CT and the extent of resection was expressed as the RLV divided by total liver volume (TLV). Liver and spleen hypertrophy were expressed according to the absolute gain or relative increase in the initial volumes (%).The presence of fibrosis >F1, associated extrahepatic resection (except minor resections), and previous hepatectomy (major or minor) within 3 months represented exclusion criteria.

Mean ± standard deviation (SD) liver volume at 1 month was higher than RLV (1187 ± 286 cm(3) versus 764 ± 421 cm(3) ; P < 0.001). Mean ± SD splenic volume increased from 252 ± 100 cm(3) preoperatively to 300 ± 111 cm(3) at 1 month (P < 0.001). Liver and splenic hypertrophy were significant after major hepatectomies (+100% and +26%, respectively; P < 0.001), but not after minor hepatectomies. Liver hypertrophy was inversely correlated to RLV/TLV (r = -0.687, P < 0.001). Splenic hypertrophy was not correlated to RLV/TLV. Liver and splenic hypertrophy were linearly correlated (r = 0.495, P < 0.001). Neoadjuvant chemotherapy (n = 37), preoperative portal vein embolization (n = 10) and postoperative complications (overall: n = 25; major: n = 10; infectious: n = 6) had no impact on hepatic or splenic hypertrophy.

Splenic hypertrophy occurred after major hepatectomy, but was not correlated to the extent of resection, by contrast with liver hypertrophy. Nevertheless, there was a linear correlation between splenic and liver hypertrophy. This correlation suggests the hypothesis of a splenic action of hepatic growth factors or a redistribution of the total reticuloendothelial system rather than an effect of reduction of the portal bed or hepatic outflow.

Severe sepsis is associated with early release of inflammatory mediators that contribute to the morbidity and mortality observed during the first stages of this syndrome. Although sepsis is a deadly, acute disease, high mortality rates have been observed in patients displaying evidence of sepsis-induced immune deactivation. Although the contribution of experimental models to the knowledge of pathophysiological and therapeutic aspects of human sepsis is undeniable, most of the current studies using animal models have focused on the acute, proinflammatory phase. We developed a murine model that reproduces the early acute phases but also the long-term consequences of human sepsis. We induced polymicrobial acute peritonitis (AP) by establishing a surgical connection between the cecum and the peritoneum, allowing the exit of intestinal bacteria. Using this model, we observed an acute phase with high mortality, leukopenia, increased interleukin-6 levels, bacteremia, and neutrophil activation. A peak of leukocytosis on day 9 or 10 revealed the persistence of the infection within the lung and liver, with inflammatory hepatic damage being shown by histological examination. Long-term (20 days) derangements in both innate and adaptive immune responses were found, as demonstrated by impaired systemic tumor necrosis factor alpha production in response to an inflammatory stimulus; a decreased primary humoral immune response and T cell proliferation, associated with an increased number of myeloid suppressor cells (Gr-1(+) CD11b(+)) in the spleen; and a low clearance capacity. This model provides a good approach to attempt novel therapeutic interventions directed to augmenting host immunity during late sepsis.

To evaluate the contribution of the liver to total circulatory reticuloendothelial system (RES) phagocytosis capacity in patients undergoing liver resection and to compare it with values in end-stage chronic liver disease.

The mechanism whereby major liver resection is associated with a high incidence of infection is unknown. Significant impairment of RES phagocytosis has been described in liver failure, rendering such patients susceptible to infection; and we hypothesized that similar impairment might occur following major liver resection.

A prospective study was conducted in which Tc-albumin microspheres blood clearance served as a parameter for RES phagocytosis and was studied together with indocyanine green blood clearance, actual liver volume measured by three-dimensional image analysis, and a clinical score of hepatic dysfunction in 17 patients undergoing liver resection and in 8 patients with end-stage chronic liver disease assessed for liver transplantation.

When expressed relative to volume unit of residual liver, microspheres clearance increased significantly in the immediate postoperative period (day 1) following major (0.009% versus 0.022% min(-1) mL(-1), P < 0.001), but not minor liver resection. In contrast, the absolute rate of microsphere clearance decreased following major resection (15% min(-1) versus 10% min(-1), P < 0.001) and was comparable with the rate observed in end-stage chronic liver disease (9% min(-1)). This decrease in circulatory microspheres clearance after resection paralleled a decrease in indocyanine green clearance (R2 = 0.511, P = 0.006), and there was a trend for those with moderate liver dysfunction to have lower microspheres clearance rates (P = 0.068).

Preservation of a minimum volume of functioning liver is a prerequisite for adequate RES phagocytosis capacity, and failure of this system may predispose patients undergoing major liver resection to infection as observed in clinical studies.

Translocating enteric bacteria have been suggested as playing a major role in the development of infections after partial hepatectomy. We investigated the effect of N-acetylcysteine (NAC) on bacterial translocation (BT) and intestinal mucosa as the first line of defense against BT.

We compared four groups of eight Sprague-Dawley male rats each: sham, control (partially hepatectomized), partial hepatectomy plus preoperative single-dose NAC, and a fourth that received partial hepatectomy with a preoperative single-dose NAC plus treatment with NAC for 2 days. Microorganism counts of tissues, lung injury score, lung tissue glutathione, and malondialdehyde levels and microscopy of intestinal mucosa were studied at the end of 48 h.

Microorganism count in the lung and mesenteric lymph node cultures and lung injury score were significantly higher in the control group when compared with the sham, third, and fourth groups (lung: 9919.6 versus 0.0, 2912.9, 1550.0 cfu/g tissue; mesenteric lymph nodes: 8458.3 versus 0.0, 89.0, 88.9 cfu/g tissue; lung injury score: 3.25 versus 0.5, 1.13, 1.75). In the control group, the villous height of the distal ileal mucosa was significantly shorter than the sham group (65.25 versus 75.25 microm) and the difference from groups 3 and 4 was not statistically significant. Neutrophil infiltration in the distal ileal mucosa of the control group was significantly higher than the sham, third and fourth groups (3.13 versus 0.25, 0.38 and 1.0).

The parenteral use of NAC attenuates bacterial translocation after partial hepatectomy in rats. Attenuation of the lung injury after partial hepatectomy in NAC-treated groups might be attributable to both anti-inflammatory effect and the effect on BT.

The understanding and treatment of acute hepatic failure has developed rapidly over the last 40 years reducing morbidity and mortality from this syndrome. Progress has been made by the study of animal models that reflect the clinical, biochemical and histological pattern of the syndrome seen in man. This is of increasing importance with the use of therapeutic intervention, liver transplantation and the use of extra-corporeal liver support devices. This review examines and critically appraises the various approaches to the study of acute hepatic failure in animal models, including both surgical and pharmacological approaches.

Pancreatitis-associated pulmonary injury is still associated with substantial mortality, especially when seen as a part of the multiple organ dysfunction syndrome.

The present study aimed at evaluating alterations in type II pneumocytes and the potential relationship with the development of pulmonary injury after acute haemorrhagic pancreatitis induced by an intraductal infusion of 5% sodium taurodeoxycholate in the rat.

The results demonstrated that definite alterations in type II pneumocytes were noted 12 and 24 h after induction of pancreatitis, characterized by an increase in the number of vocalized lamellae, the exposed area of type II pneumocytes to alveolar airspace, cellular separation and apoptosis without alterations in cellular membrane integrity. Dysfunction of the pulmonary endothelial barrier was evidenced by an increase in pulmonary albumin flux and the leakage index as well as the migration of lanthanum probes from capillaries to interstitial tissues. The levels of tumour necrosis factor (TNF) in bronchoalveolar lavage fluid significantly increased during the initial phase (3 and 6 h) after pancreatitis. The phagocytic activity of the pulmonary custocyte system increased 3 and 12 h after induction of pancreatitis.

Thus, pulmonary endothelial barrier dysfunction, an activated custocyte system, and initial release of TNF seems to be involved in the pathogenesis of pancreatitis-associated type II pneumocyte compromise.

This study investigated the effects of chronic ethanol intake on hepatic haemodynamics and reticuloendothelial system function in the rat. Comparisons were also made with blood flow to pancreas, kidney, spleen, lung and skin. Male Wistar rats, approximately 0.15 kg initial body weight, were fed a diet containing 35% of the total calories as ethanol. Controls were pair-fed identical amounts of the same diet in which ethanol was replaced by isocaloric glucose. The hepatic perfusion index and reticuloendothelial function was determined with [(99m) Tc]-labelled sulphur colloid [(99m) Tc]-SC) and blood flow with radiolabelled microspheres under anaesthesia. After 4-5 weeks the weights of liver and skin of alcohol fed rats decreased by 10% (p= 0.040) and 23% (p= 0.024), respectively, compared to controls and there was a small increase in kidney weight (15%, p = 0.001). Blood flow to liver, pancreas, kidney, spleen, lung and skin was not altered significantly by chronic alcohol administration, irrespective of whether the data were expressed as a percentage of cardiac output, blood flow per minute per organ or blood flow per minute per g tissue weight (p > 0.113 in all instances). However, there was a significant increase in splenic reticuloendothelial system activity (+ 121%, p = 0.018). Hepatic reticuloendothelial system activity was also increased (+ 22%, p = 0.061). Chronic alcohol administration resulted in significant increases in portal pressure (+ 55%, p = 0.042) and portal venous resistance (+ 66%, p = 0.001), but portal venous inflow and hepatic perfusion index were not altered compared to controls The results of this study indicated that chronic alcohol administration did not alter visceral blood flow significantly, but did increase portal pressure, portal vascular resistance and reticuloendothelial system activity.

Reticuloendothelial system function, as assessed by clearance of radiolabelled bacteria, was evaluated in acute liver injury induced by D-galactosamine in rats, and compared with that after 70% liver resection model.

Reticuloendothelial system function was significantly impaired in both instances, but the extent and the pattern of reticuloendothelial system impairment differed in the two models. While the elimination rate of the radiolabelled bacteria (k-value) decreased in both the liver resection and D-galactosamine groups (19% and 52%, respectively), the corrected phagocytic index (alpha) increased in 70% liver resection (247%), indicatine increased activity among the remaining reticuloendothelial system cells of the liver. Estimation of subserosal organ blood flow showed decreased flow to the cecum and distal small intestine (correction of intesting) in both groups, whereas it was significantly increased (477%) in the remaining parts of the liver in the liver resection group.

These findings show that reticuloendothelial system activity is deranged in both these groups, which may explain the increased occurrence of bacterial complications observed in corresponding clinical conditions.

Bacterial infection and bacteremia are common complications in patients with acute liver failure. Bacterial translocation from the gut has been suggested to be a major cause of bacterial infections in experimental acute liver failure. In the present study, a water-soluble ethylhydroxyethyl cellulose (EHEC) was administered orally 1 and 24 hours prior to 90% hepatectomy in the rat in order to prevent bacterial translocation in experimental acute liver failure induced by subtotal liver resection in the rat. Ninety percent hepatectomy alone resulted in 80 to 100% translocation to mesenteric lymph nodes or blood 2 and 4 hours after operation. There was no translocation in rats undergoing sham operation or 90% hepatectomy with EHEC administration prior to operation (p < .01). Bacterial overgrowth, increased bacterial adherence onto the intestinal surface, and diminished intestinal and mucosal mass were also observed in animals with subtotal liver resection, but not in those administered EHEC. A delayed 2-hour intestinal transit time occurred in both groups receiving subtotal liver resection, with or without oral EHEC. EHEC inhibited bacterial growth and DNA synthesis and altered bacterial surface properties after 1-hour incubation with bacteria in vitro, an interaction that was not further influenced by time. These results imply that EHEC may alter enterobacterial capacities of metabolism, proliferation, and invasion by effects on the bacterial surface. Furthermore, EHEC seems to possess a trophic action on the intestine, though without enhancing the intestinal motility.

Bacterial translocation from the gut to extraintestinal sites has been demonstrated as a mechanism explaining bacterial infectious complications after various insults.

To explore the potential therapeutic value of water-soluble ethylhydroxyethyl cellulose (EHEC). Its effects on macrophage phagocytic capacity, bacterial adherence on the intestinal surface, and bacterial growth were evaluated both in vivo and in vitro.

Preoperative administration of EHEC reduced the incidence of bacterial translocation from the gut to mesenteric lymph nodes and blood and prevented overgrowth by enteric bacteria after 70% or 90% hepatectomy. Uptake of macrophages harvested from blood decreased after intravenous administration of EHEC. EHEC diminished the otherwise increased bacterial adherence on the intestinal surface induced by major liver resection. EHEC in bacterial cultures for over 1 h was capable of inhibiting bacterial growth and delaying bacterial DNA synthesis in vitro.

The present study indicates that EHEC could be a potential agent for the prevention of gut-origin sepsis.