Early Hepatic Injury Research Articles

Ginsenoside Rg3 Attenuates Early Hepatic Injury via Inhibiting PPARγ- and Ang II-Related Inflammation and Fibrosis in Type II Diabetic Mice

Ginsenoside Rg3 (Rg3), a natural product abundantly present in Korean Red Ginseng, is widely known for its anti-tumor activity. In our previous studies, we had further demonstrated that Rg3 has protective effects on the hearts, kidneys, and aortas of animals with hypertension or hypercholesterolemia, and its main mechanisms include down-regulation of angiotensin II (Ang II) levels and activation of peroxisome proliferator-activated receptor gamma (PPARγ) pathway in those tissues. In this study, the protective effects of Rg3 on liver were determined in db/db mice, a most recognized type II diabetes (T2DM) animal model with nonalcoholic fatty liver disease (NAFLD). The results showed that Rg3 did not have obvious effects to the body weight, blood glucose, and lipids of db/db mice. According to the results of histology examination, Rg3 could not improve steatosis in the hepatic tissue, too. But Rg3 did attenuate alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation in serum and collagen deposition in hepatic tissue. Immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) showed that Rg3 upregulated PPARγ and downregulated Ang II in hepatic tissue in db/db mice, which resulted in reducing activities of transforming growth factor β (TGF-β)/connective tissue growth factor (CTGF) pathway, downregulating the levels of inflammatory cytokines and attenuating collagen accumulation. In conclusion, although it has no obvious effect on steatosis in the hepatic tissue, Rg3 indeed attenuates early hepatic injury from NAFLD via inhibiting PPARγ- and Ang II-related inflammation and fibrosis in T2DM db/db mice. These effects are independent of reducing blood glucose and lipids, and the mechanisms are similar to the protective effects of Rg3 in hypertension and hypercholesterolemia animals in our previous studies.

Association of novel markers of liver disease with neonatal liver disease in premature baboons, Papio sp.

Parenteral Nutrition (PN) Associated Liver Disease (PNALD) affects up to 60% of neonates; however, techniques for diagnosing and monitoring disease progression remain limited. The neonatal baboon model may provide a unique opportunity to identify serologic markers associated with this disease. The purpose of this study was to investigate if Hyaluronic Acid (HA), TIMP metallopeptidase inhibitor 1 (TIMP1), Amino-terminal Propeptide of Type-III Collagen (PIIINP) and Enhanced Liver Fibrosis (ELF) score associate with histological liver disease in neonatal baboons exposed to PN. Preterm baboons delivered via c-section at 67% gestation received PN for 14 days with or without Intralipid (PRT+IL, PRT-IL, respectively) or were sacrificed after birth (PRTCTR). Term baboons were sacrificed after birth (TERMCTR) or survived 14 days (TERM+14d). Serum HA, TIMP1, and PIIINP concentrations were measured by ELISA. A blinded pathologist assigned liver histological scores following necropsy. HA increased 9.1-fold, TIMP1 increased 2.2-fold, and ELF score increased 1.4-fold in PRT-IL compared to PRTCTR. ALT, AST, and GGT were within normal limits and did not vary between groups. A trend towards increased fibrosis was found in PRT-IL baboons. Microvesicular hepatocyte steatosis and Kupffer cell hypertrophy were elevated in PRT-IL vs PRTCTR. HA and TIMP1 were significantly elevated in preterm baboons with early histological findings of liver disease evidenced by hepatic steatosis, Kupffer cell hypertrophy and a trend towards fibrosis whereas traditional markers of liver disease remained normal. These novel markers could potentially be utilized for monitoring early hepatic injury in neonates.

Dolutegravir induced sub-acute hepatic failure in HIV positive treatment naïve man in Botswana

Dolutegravir associated hepatic failure has rarely been reported. Hepatic failure can occur either acutely or after few weeks as it happened in our patient. We report a case of 61 years old HIV-positive treatment naïve patient who started experiencing features of hepatic injury one month after starting Dolutegravir-based regimen. Patient presented late with overt hepatic failure. We emphasize the importance of close monitoring both at initiation and long-term so as identify patients with early hepatic injury and limit fatal outcomes which are potentially avoidable.

Liver involvement in the process of acute respiratory infections in pediatric patients

We aimed to investigate the prevalence of liver involvement in pediatric patients with ARI using both routine tests of hepatic panel, and ornithine carbamoyltransferase (OCT) to identify the most sensitive indicators of early hepatic injury. A prospective cohort study of 84 armenian children with ARI was conducted to evaluate the associated liver involvement. The diagnostic variables of interest were the signs of clinical disease severity, and enzymatic profile of the patients. Serum levels of OCT were increased in 94% of patients versus routine tests of hepatic panel (AST in 41.7%, ALT in 15.5%, etc). Variance analysis by severity groups showed the serum levels of OCT (p < 0.001), ammonia (p < 0.001), phospholipides (p = 0.05), glucose (p = 0.01), TNF-α (p = 0.01), IL-8 (p < 0.001), AST (p < 0.001), and ALP (p < 0.001) were associated with the severity of underlying disease. Moreover, regression analysis revealed the serum activity of OCT (p value < 0.001, OR = 1.27) and ammonia (p value 0.002, OR = 1.1) significantly predict the severity of the disease. Using more sensitive marker of liver damage can detect more cases of ARI with hepatic manifestations. For evaluation of the liver involvement we are suggesting the testing of serum OCT levels as a more sensitive and specific marker. Pediatric patients with ARI and with higher serum OCT levels have 27% more chance to experience increased disease severity, which can affect on liver state and prolong hospitalization time and cost.

Utility of Serum miR-122, Liver Enzymes, and Hepatic Histopathology in Response to Hepatotoxicants in Sprague-Dawley Rats.

More than 80,000 chemicals are in commercial use worldwide. Hepatic metabolism to toxic intermediates is often a key mechanism leading to tissue damage and organ dysfunction. Effective treatment requires prompt detection of hepatotoxicity, ideally with rapid, minimally invasive diagnostic assays. In this study, archetypal histologic features of chemically induced hepatic injury were compared with clinical chemistries (including liver enzymes) and serum concentrations of microRNA-122 (miR-122, the processed form miR-122-5p), a biomarker of liver injury. The hepatotoxicants 4,4'-methylenedianiline (4,4'-MDA), allyl alcohol (AA), or carbon tetrachloride (CCl4) were orally administered to male Sprague-Dawley rats for 1, 5, 14, or 28 days to induce liver damage. Formalin-fixed, paraffin-embedded liver sections were evaluated histologically for inflammation, fibrosis, necrosis, and lipid accumulation. Liver enzymes were measured in serum, and serum miR-122 concentrations were assessed by quantitative polymerase chain reaction (qPCR). Histologic features of hepatic injury dose-dependently increased in both severity and frequency. Increases in liver enzymes and bilirubin were more pronounced in response to AA or 4,4'-MDA than to CCl4 at early time points. Elevated serum miR-122 levels in animals administered CCl4, AA, or 4,4'-MDA were more strongly associated with degree of hepatic histopathology than with dosage. Given this sensitive expression pattern postexposure, liver-specific miR-122 may improve the diagnostic accuracy of early hepatic injury.

Activation of hepatic stem cells compartment during hepatocarcinogenesis in a HBsAg HBV-transgenic mouse model

Chronic infection of Hepatitis B Virus (HBV) is one of the highest risk factors of hepatocellular carcinoma (HCC). The accumulation of HBV surface antigen (HBsAg) into hepatocytes induces inflammation and oxidative stress, impairing their replicative ability and allowing the activation of the hepatic stem cells (SC) compartment. This study aimed to understand the involvement of SC during hepatocarcinogenesis in HBsAg-related liver damage, from early injury until HCC. HBsAg-transgenic (TG) and wild type (WT) mouse were followed at several stages of the liver damage: inflammation, early hepatocytes damage, dysplasia, and HCC. Serum transaminases, liver histology, and diagnostic data were collected. The expressions of SC and cancer stem cells (CSC) markers was analyzed by RT-qPCR, immunohistochemistry and Western blot. Starting from 3 months, TG animals showed a progressive liver damage characterized by transaminases increase. The up-regulations of SCs markers Cd34 and Sca-1 started from the beginning of the inflammatory stage while progressive increase of Krt19 and Sox9 and CSCs markers Epcam and Cd133 from early hepatic injury. The expressions of Cd133, Cd34, and Afp were significantly higher in HCC compared to paired non-HCC tissue, in contrast to Epcam and Krt19. Western blot and IHC confirmed the positivity of Cd34 and Cd133 in small cells subpopulation.

Inhibition of Plexin C1 Protects Against Hepatic Ischemia-Reperfusion Injury.

Hepatic ischemia-reperfusion injury is a disease pattern that is associated with an acute inflammatory reaction. It is well known that neutrophils play an essential role in the early phase of hepatic ischemia-reperfusion injury and determine the extent of tissue damage. Hepatic ischemia-reperfusion injury can result in organ failure, which is linked to high mortality. Recent data indicate that the neuronal guidance receptor Plexin C1 is involved in the control of the acute inflammatory response and, as such, modulates the transmigration of neutrophils. Hence, we investigated the functional role of Plexin C1 in a mouse model of early hepatic ischemia-reperfusion injury. Animal study. University experimental laboratory. Wild-type, PLXNC1 and chimeric mice. Hepatic ischemia-reperfusion injury or sham operation. We found that the functional inhibition of Plexin C1 in wild-type mice treated with an anti-Plexin C1 antibody and a Semaphorin 7A peptide reduced hepatic ischemia-reperfusion injury, as measured by the levels of lactate dehydrogenase, aspartate, and alanine aminotransferase. This reduction in ischemia-reperfusion injury was accompanied by reduced numbers of neutrophils in ischemic hepatic tissue and reduced serum levels of inflammatory cytokines. Experiments using Plexin C1 receptor-deficient (PLXNC1) mice also demonstrated decreased hepatic ischemia-reperfusion injury. Studies of chimeric mice revealed that the hematopoietic Plexin C1 knockout is crucial for reducing the extent of hepatic ischemia-reperfusion injury. These results describe a role for Plexin C1 during ischemia-reperfusion injury, highlight the role of hematopoietic Plexin C1 in the development of hepatic ischemia-reperfusion injury, and suggest that Plexin C1 is a potential drug target.

MicroRNA-674-5p/5-LO axis involved in autoimmune reaction of Concanavalin A-induced acute mouse liver injury.

Autoimmune hepatitis is characterized, in part, by the pathways involving cysteinyl-leukotriene metabolites of arachidonic acid, the dynamics of which remain unclear. Here, we explored post-transcriptional regulation in the 5-lipoxygenase (5-LO) pathway of arachidonic acid in a Concanavalin A (Con A) induced mouse model. We found that Con A administration lead to 5-LO overexpression and cysteinyl-leukotriene release in early hepatic injury, which was attenuated by cyclosporin A pretreatment. Subsequent microarray and qRT-PCR analysis further showed that microRNA-674-5p (miR-674-5p) displayed a significant decrease in expression in Con A-damaged liver. Noting that miR-674-5p harbors a potential binding region for 5-LO, we further transfected hepatic cell lines with overexpressing miR-674-5p mimic and discovered a negative regulating effect of miR-674-5p on 5-LO expression in the presence of IL-6 or TNF-α. These findings suggest that miR-674-5p might be a negative regulator in 5-LO mediated autoimmune liver injury, representing a compelling avenue towards future therapeutic interventions.

Therapeutic mechanisms of adjunct peritoneal resuscitation for the early hepatic injury in rats after hemorrhagic shock

Objective To investigate the therapeutic effect of adjunct peritoneal resuscitation (APR) on the early hepatic injury in rats with hemorrhagic shock in order to explore its possible mechanisms. Methods Ninety-six male Wistar rats were assigned randomly (random number) into control group, shock group, APR1 group and APR2 group. Each group was further divided into 3 subgroups (n=8 in each) as per the animals sacrificed separately at 1 h, 2 h, and 6 h after resuscitation. The rat model of hemorrhagic shock was made by exsanguination under amytal anesthesia and heparinization. The rats in shock group received shed blood plus twice amount of normal saline as conventional intravenous resuscitation (CIR). Besides CIR, at the beginning of resuscitation, those rats in APR1 and APR2 groups were administered intra-peritoneally with 100 mL/kg of Ringer's solution or 2.5% glucose-based peritoneal dialysis solution, respectively. The shock rats in the four groups were sacrificed separately at above mentioned intervals after resuscitation. Liver enzymes and wet/dry weight ratio (W/D) of liver tissue were measured, and pathological changes of liver tissue were observed under optic microscope. The expressions of NF-κB and hot shock protein-70 (HSP70) mRNA in the liver tissue of rats were detected with RT-PCR. All data were statistically analyzed using SPSS 16.0 software. Results Compared with the shock group and APR1 group, the expressions of HSP70 mRNA in the liver tissue of rats at all given intervals after resuscitation in APR2 group increased significantly (P <0.05) , but the W/D ratios of liver tissue at 2 h, 6 h, the degree of pathological changes of liver tissue in 6 h, serum levels of ALT and AST at all given intervals and the expressions of NF-κB mRNA at all given intervals decreased significantly (P <0.05). Conclusions APR with 2.5% glucose-based peritoneal dialysis solution can significantly mitigate the early hepatic injury secondary to hemorrhagic shock, and the mechanisms may be associated with enhancement the expressions of HSP70 mRNA and inhibition the expressions of NF-κB mRNA. Key words: Adjunct peritoneal resuscitation; Hemorrhagic shock; Nulear factor kappa B; Heat- shock protein 70; Hepatic lesion; Peritoneal dialysis fluid; Liver function; Wet/dry weight ratio (W/D) of liver tissue

Cell Ultrastructure and Distribution of Trifluoroacetylated Protein-Adducts in Early Hepatic Injury in Mice Induced by Inhalation Anesthetic, Halothane.

An abstract is not available for this content so a preview has been provided. As you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Matrix Metalloproteinase-12 Cleaves Tenascin-C and Mediates Early Hepatic Ischemia-Reperfusion Injury.

Matrix Metalloproteinase-12 Cleaves Tenascin-C and Mediates Early Hepatic Ischemia-Reperfusion Injury.

Role of liver fatty acid binding protein in hepatocellular injury: Effect of CrPic treatment

This study was designed to investigate the molecular mechanisms of chromium picolinate (CrPic, Fig. 1) hepatoprotective activity from alloxan-induced hepatic injury. Diabetes is induced by alloxan-treatment concurrently with the hepatic injury in mice. In this study, we investigate the protective effect of CrPic treatment in hepatic injury and the signal role of liver fatty acid binding protein in early hepatocellular injury diagnostics. In this study, alanine aminotransferase (ALT; EC 2.6.1.2) and aspartate aminotransferase (AST; EC 2.6.1.1) levels in the alloxan group were higher 71% and 50%, respectively, than those of the control group (ALT: 14.51±0.74; AST: 22.60±0.69). The AST and ALT levels in CrPic group were of minimal difference compared to the control groups. Here, CrPic exhibited amelioration alloxan induced oxidative stress in mouse livers. A significant increase in liver fatty acid-binding protein (L-FABP) was observed, which indicates increased fatty acid utilization in liver tissue [1]. In this study, the mRNA levels of L-FABP increased in both the control (1.1 fold) and CrPic (0.78 fold) groups compared the alloxan group. These findings suggest that hepatic injury may be prevented by CrPic, and is a potential target for use in the treatment of early hepatic injury.

Brassica rapa L. extract alleviate early hepatic injury in alloxan-induced diabetic rats

Liver insufficiency is one of the most important consequences of diabetes mellitus. The main objective of this study was to evaluate the protective effect of turnip root ethanolic extract (TREE) on early hepatic injuries in alloxanized-diabetic rats. Eighty male Wistar rats were randomly assigned into 4 equal groups including: normal healthy, normal+TREE, diabetic and 4- diabetic+TREE. Diabetes was induced with a single injection of alloxan (120 mg/kg i.p.). TREE treatment groups received TREE (200 mg/kg) daily for 8 weeks by means of gavage. At the end of the experimental period, levels of functional liver markers [aspartate aminotransaminase (AST), alanine aminotransaminase (ALT) and lactate dehydrogenase (LDH)], TB, albumin and total protein (TP) were assessed in the serum. Product of lipid peroxidation (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GR) activity was also assayed in liver homogenates. Finally, the biochemical findings were matched with histopathological verification. Statistically, the quantitative data obtained were compared among the groups by one-way analysis of variance followed by Turkey post-hoc test. Statistical significance was considered as p<0.05. In the diabetic rats, TREE significantly decreased the levels of serum biomarkers of hepatic injury. Furthermore, TREE significantly decreased the lipid peroxidation and elevated the decreased values of antioxidant enzymes in diabetic rats. Histopathologically, the changes were parallel to the biochemical findings. The results obtained showed that TREE alleviates early hepatic injuries in the rats with experimentally induced diabetes. Key words: Brassica rapa L., diabetes, hepatic injury, alloxan, rats.

Tumor necrosis factor signaling in hepatocyte apoptosis

Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, and cancer. Our aim was to clarify the protective pathway in death receptor-mediated hepatocyte apoptosis and the significance of apoptosis in liver injury. In vitro: AdIkappaBsr plus tumor necrosis factor (TNF)-alpha/Jo2 rapidly induced apoptosis in mouse hepatocyte, whereas TNF-alpha/Jo2 alone produced little cytotoxicity. The combination of the mitochondrial permeability transition (MPT) inhibitors, cyclosporine A and trifluoperazine, protected AdIkappaBsr-infected hepatocytes from TNF-alpha- but not Fas-mediated apoptosis. The TNF-alpha and Jo2 induced iNOS through NF-kappaB. Nitric oxide donor (S-nitroso-N-acetylpenicillamine) inhibited Bid cleavage, the MPT, and caspase activation and reduced TNF-alpha- and Fas-mediated cell killing. Inhibition of PI3K by LY294,002 and a dominant-negative Akt, which attenuated NF-kappaB activation by TNF-alpha or Jo2, sensitized hepatocytes to TNF- or Jo2. In vivo: apoptosis as well as necrosis may play an important role in hepatic ischemia/reperfusion injury. Adenoviral gene transfer of myrAkt could inhibit apoptotic cell death and subsequent hepatic ischemia/reperfusion injury in the rat, through Bad not NF-kappaB. Bile acids cause liver injury during cholestasis by inducing hepatocyte apoptosis. Hepatocyte apoptosis has a major role in hepatic injury by bile duct ligation. At least, early hepatic injury by bile duct ligation involved Fas-mediated and Bcl-xL insensitive apoptotic pathway. In conclusion, the role of apoptosis in various liver diseases may suggest possible treatments.

A caspase inhibitor, IDN-6556, ameliorates early hepatic injury in an ex vivo rat model of warm and cold ischemia

This study examined the efficacy of the caspase inhibitor, IDN-6556, in a rat model of liver ischemia-reperfusion injury. Livers from male Sprague-Dawley rats were reperfused for 120 minutes after 24 hours of 4 degrees C cold storage in University of Wisconsin solution. Portal blood flow measurements estimated sinusoidal resistance, and bile production, alanine aminotransferase activities, and Suzuki scores were evaluated as parameters of hepatocyte/liver injury. Treated livers were exposed to 25 or 50 microM of IDN-6556 in University of Wisconsin storage solution and/or the perfusate. All treatment regimens with IDN-6556 significantly improved portal blood flow measured at 120 minutes, and significant improvements were seen as early as 30 minutes when inhibitor was also present in the perfusate (P < 0.01). All treatment groups with IDN-6556 significantly increased bile production by 3-4-fold compared with controls (P < 0.01), and reductions in alanine aminotransferase activities were seen within 90 minutes of reperfusion (P < 0.05). These data were confirmed by improved Suzuki scores (less sinusoidal congestion, necrosis, and vacuolization) in all treated groups. Livers from the IDN-6556-treated groups had markedly reduced caspase activities and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells, suggesting reductions in apoptosis. IDN-6556 present in cold storage media ameliorated liver injury due to cold ischemia and reperfusion injury and may be a rational therapeutic approach to reduce the risk of liver ischemia in the clinical setting.

Comment on "Endothelially Derived Nitric Oxide Affects the Severity of Early Acetaminophen-induced Hepatic Injury in Mice"

Comment on "Endothelially Derived Nitric Oxide Affects the Severity of Early Acetaminophen-induced Hepatic Injury in Mice"

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

An impaired immunologic response to infection has been recognized as a major defect in the pathogenesis of sepsis and multi-organ failure. Sepsis-associated liver dysfunction and damage are main determinants for the course of the disease. CpG-motif-containing DNA-sequences (CpG-ODN) were previously shown to confer protection in models of infection by stimulating both innate and specific immune responses. Herein, we studied the effect of CpG-ODN in lipopolysaccharide (LPS)-associated hepatotoxicity. Sprague Dawley rats pre-treated at day 6 with either CpG-ODN or inert DNA were challenged with E. coli LPS and subsequently studied for liver injury at 6 and 16 h using in vivo fluorescence microscopy and immunohistochemistry. Western blot protein analysis served for assessment of expression of TLR4, TNF receptor-associated factor 6 (TRAF6), NFkappaB and caspase-3. To evaluate CpG-ODN effects during non-septic conditions, additional animals were solely exposed to CpG-ODN and studied after 1 and 6 days. CpG-ODN application induced marked hepatic microcirculatory deterioration and liver dysfunction at day 1, however, with almost complete recovery to normal at day 6. Interestingly, CpG-ODN pre-treatment decreased LPS-induced leukocyte-endothelial cell interaction, sinusoidal perfusion failure and caspase-3-dependent apoptotic cell death. Although Kupffer cell phagocytic activity was not affected, CpG-ODN pre-treatment in LPS-challenged animals attenuated hepatic protein expression of TRAF6 and NFkappaB and increased TLR4 by almost 100%. CpG-containing DNA-sequences induce early hepatic injury, but mediate long-term protection against LPS hepatotoxicity. The mechanism of protection is based on the induction of cross-tolerance, probably via inhibition of the downstream TRAF6-NFkappaB signaling pathway and upregulation of the TLR4 surface receptor.

Early hepatic microvascular injury in response to acetaminophen toxicity.

The hepatic toxic response to acetaminophen (APAP) is characterized by centrilobular (CL) necrosis preceded by hepatic microvascular injury and congestion. The present study was conducted to examine changes in liver microcirculation after APAP dosing. Male C57Bl/6 mice were treated with APAP (600 mg/kg body weight) by oral gavage. The livers of anesthetized mice were examined using established in vivo microscopic methods at 0, 0.5, 1, 2, 4, 6, 12 hours after APAP. The levels of hepatic transaminases (i.e., alanine aminotransferase [ALT] and aspartate transaminase) increased minimally for up to 2 hours. Thereafter, their levels were significantly and progressively increased. The numbers of swollen sinusoidal endothelial cells (SECs) in periportal regions were increased (3.5-fold) from 0.5 to 6 hours, and those in CL regions were increased (4.0-fold) at 0.5 and 1 hour. The intensity of in vivo staining for formaldehyde-treated serum albumin, which is a specific ligand for SECs, was reduced from 2 to 12 hours. Erythrocytes infiltrated into the space of Disse as early as 2 hours, and the area occupied by these cells was markedly increased at 6 hours. Sinusoidal perfusion was reduced from 1 through 12 hours, with a nadir (35% decrease) at 4 and 6 hours. Phagocytic Kupffer cell activity was significantly elevated from 0.5 through 12 hours. Although gadolinium chloride minimized the changes in sinusoidal blood flow and reduced ALT levels 6 hours after APAP, it failed to inhibit endothelial swelling, extravasation of erythrocytes, and CL parenchymal necrosis. These results confirm that APAP-induced SEC injury precedes hepatocellular injury, supporting the hypothesis that SECs are an early and direct target for APAP toxicity. These findings also suggest that reduced sinusoidal perfusion and increased Kupffer cell activity contribute to the development of APAP-induced liver injury.

Early Hepatic Microvascular Injury in Response to Acetaminophen Toxicity

Objective: The hepatic toxic response to acetaminophen (APAP) is characterized by centrilobular (CL) necrosis preceded by hepatic microvascular injury and congestion. The present study was conducted to examine changes in liver microcirculation after APAP dosing. Methods: Male C57Bl/6 mice were treated with APAP (600 mg/kg body weight) by oral gavage. The livers of anesthetized mice were examined using established in vivo microscopic methods at 0, 0.5, 1, 2, 4, 6, 12 hours after APAP. Results: The levels of hepatic transaminases (i.e., alanine aminotransferase [ALT] and aspartate transaminase) increased minimally for up to 2 hours. Thereafter, their levels were significantly and progressively increased. The numbers of swollen sinusoidal endothelial cells (SECs) in periportal regions were increased (3.5-fold) from 0.5 to 6 hours, and those in CL regions were increased (4.0-fold) at 0.5 and 1 hour. The intensity of in vivo staining for formaldehyde-treated serum albumin, which is a specific ligand for SECs, was reduced from 2 to 12 hours. Erythrocytes infiltrated into the space of Disse as early as 2 hours, and the area occupied by these cells was markedly increased at 6 hours. Sinusoidal perfusion was reduced from 1 through 12 hours, with a nadir (35% decrease) at 4 and 6 hours. Phagocytic Kupffer cell activity was significantly elevated from 0.5 through 12 hours. Although gadolinium chloride minimized the changes in sinusoidal blood flow and reduced ALT levels 6 hours after APAP, it failed to inhibit endothelial swelling, extravasation of erythrocytes, and CL parenchymal necrosis. Conclusions: These results confirm that APAP-induced SEC injury precedes hepatocellular injury, supporting the hypothesis that SECs are an early and direct target for APAP toxicity. These findings also suggest that reduced sinusoidal perfusion and increased Kupffer cell activity contribute to the development of APAP-induced liver injury.

Does isovolemic hemodilution improve the early hepatic reperfusion injury after warm ischemia?

Does isovolemic hemodilution improve the early hepatic reperfusion injury after warm ischemia?