Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

Autoimmune hepatitis is characterized by autoantibodies, hypergammaglobulinemia, and interface hepatitis on histological examination. The features lack diagnostic specificity, and other diseases that may resemble autoimmune hepatitis must be excluded. The clinical presentation may be acute, acute severe (fulminant), or asymptomatic; conventional autoantibodies may be absent; centrilobular necrosis and bile duct changes may be present; and the disease may occur after liver transplantation or with features that suggest overlapping disorders. The diagnostic criteria have been codified, and diagnostic scoring systems can support clinical judgment. Nonstandard autoantibodies, including antibodies to actin, α-actinin, soluble liver antigen, perinuclear antineutrophil antigen, asialoglycoprotein receptor, and liver cytosol type 1, are tools that can support the diagnosis, especially in patients with atypical features. Prednisone or prednisolone in combination with azathioprine is the preferred treatment, and strategies using these medications in various doses can ameliorate treatment failure, incomplete response, drug intolerance, and relapse after drug withdrawal. Budesonide, mycophenolate mofetil, and calcineurin inhibitors can be considered in selected patients as frontline or salvage therapies. Molecular (recombinant proteins and monoclonal antibodies), cellular (adoptive transfer and antigenic manipulation), and pharmacological (antioxidants, antifibrotics, and antiapoptotic agents) interventions constitute future directions in management. The evolving knowledge of the pathogenic pathways and the advances in technology promise new management algorithms.

Apoptosis is the predominant mechanism of liver cell death in autoimmune hepatitis, and interventions that can modulate this activity are emerging. The aim of this review was to describe the apoptotic mechanisms, possible aberrations, and opportunities for intervention in autoimmune hepatitis. Studies cited in PubMed from 1972 to 2014 for autoimmune hepatitis, apoptosis in liver disease, apoptosis mechanisms, and apoptosis treatment were examined. Apoptosis is overactive in autoimmune hepatitis, and the principal pathway of cell death is receptor mediated. Surface death receptors are activated by extrinsic factors including liver-infiltrating cytotoxic T cells and the cytokine milieu. The executioner caspases 3 and 7 cleave nuclear deoxyribonucleic acid, and the release of apoptotic bodies can stimulate inflammatory, immune, and fibrotic responses. Changes in mitochondrial membrane permeability can be initiated by caspase 8, and an intrinsic pathway of apoptosis can complement the extrinsic pathway. Defects in the apoptosis of activated effector cells can prolong their survival and sustain the immune response. Caspase inhibitors have been used in diverse experimental and human diseases to retard apoptosis. Oligonucleotides that inhibit the signaling of toll-like receptors can limit the presentation of auto-antigens, and inhibitors of apoptosis that extend the survival of effector cells can be blocked by antisense oligonucleotides. Mechanisms that enhance the clearance of apoptotic bodies and affect key signaling pathways are also feasible. Interventions that influence the survival of liver and effector cells by altering their apoptosis are candidates for study in autoimmune hepatitis.

To investigate superoxide dismutase (SOD) activity in the portal vein endothelium and malondialdehyde acid (MDA) production in liver tissue of rats submitted to 70% hepatectomy.

Twelve rats were distributed in two groups (hepatectomy and sham). Animals were sacrificed on post operative day 1 and portal vein, liver tissue and blood samples were collected. Portal vein SOD production was measured using lucigenin-amplified chemiluminescence assays. MDA measurement was used as an index of oxidative stress through the formation of TBARS (Thiobarbituric Acid Reactive Species).

There was no difference in post operative bilirubin, AST, ALT levels between groups. DHL level was higher in the hepatectomy group (p=0.01). MDA production in the remnant liver tissue and endothelial portal vein SOD activity were also significantly (p<0.05) elevated in the hepatectomy group when compared to control group. There was no correlation between MDA and SOD activity. SOD activity, on the other hand, showed a positive correlation with LDH level (p=0.038) and MDA levels showed a positive correlation with AST and ALT levels (p<0.001).

There is an increased production of malondialdehyde acid in liver tissue after partial hepatectomy and increased activity of superoxide dismutase in portal vein endothelium as well.

To investigate the role of matrix metalloproteinase (MMP)-9 in the pathogenesis of postoperative liver failure (PLF) after extended hepatectomy (EH).

An insufficient volume of the remnant liver (RL) results in higher morbidity and mortality, and a murine model with 80%-hepatectomy was used. All investigations were performed 6 h after EH. Mice were first divided into two groups based on the postoperative course (i.e., the PLF caused or did not), and MMP-9 expression was measured by Western blotting. The source of MMP-9 was then determined by immunohistological stainings. Tissue inhibitor of metalloproteinase (TIMP)-1 is the endogenous inhibitor of MMP-9, and MMP-9 behavior was assessed by the experiments in wild-type, MMP-9(-/-) and TIMP-1(-/-) mice by Western blotting and gelatin zymography. The behavior of neutrophils was also assessed by immunohistological stainings. An anti-MMP-9 monoclonal antibody and a broad-spectrum MMP inhibitor were used to examine the role of MMP-9.

Symptomatic mice showed more severe PLF (histopathological assessments: 2.97 ± 0.92 vs 0.11 ± 0.08, P < 0.05) and a higher expression of MMP-9 (71085 ± 18274 vs 192856 ± 22263, P < 0.01). Nonnative leukocytes appeared to be the main source of MMP-9, because MMP-9 expression corresponding with CD11b positive-cell was observed in the findings of immunohistological stainings. In the histopathological findings, the PLF was improved in MMP-9(-/-) mice (1.65% ± 0.23% vs 0.65% ± 0.19%, P < 0.01) and it was worse in TIMP-1(-/-) mice (1.65% ± 0.23% vs 1.78% ± 0.31%, P < 0.01). Moreover, neutrophil migration was disturbed in MMP-9(-/-) mice in the immunohistological stainings. Two methods of MMP-9 inhibition revealed reduced PLF, and neutrophil migration was strongly disturbed in MMP-9-blocked mice in the histopathological assessments (9.6 ± 1.9 vs 4.2 ± 1.2, P < 0.05, and 9.9 ± 1.5 vs 5.7 ± 1.1, P < 0.05).

MMP-9 is important for the process of PLF. The initial injury is associated with MMP-9 derived from neutrophils, and MMP-9 blockade reduces PLF. MMP-9 may be a potential target to prevent PLF after EH and to overcome an insufficient RL.

To investigate the effect of hypothermia on the function of the liver remnant (LR) after extended hepatectomy.

We performed a 75% partial hepatectomy (PH) in male C57BL/6J mice. Body temperature was measured with a rectal probe. The study mice were prospectively grouped as hypothermic (HT) or normothermic (NT) if their body temperature was < 34 °C vs ≥ 34 °C, respectively. Blood and liver samples were obtained at 24 and 48 h after 75% PH. Various factors during and after 75% PH were compared at each time point and the most important factor for a good outcome after 75% PH was determined.

At 24 and 48 h after 75% PH, LR weight was decreased in HT mice compared with that in NT mice and the assay results in the HT mice were consistent with liver failure. NT mice had normal liver regeneration. Each intra- and post-operative factor which showed statistical significance in univariate analysis was evaluated by multivariate analysis. The most important factor for a good outcome after 75% PH was body temperature at both 24 and 48 h after surgery.

Hypothermia after an extensive hepatectomy predicts impending liver failure and may be a useful clinical marker for early detection of liver failure after extended hepatectomy.

Acute liver damage is considered to be the major cause of mortality after massive hepatectomy. Prostaglandin E1 (PGE1) and somatostatin (SST) have been shown to protect against hepatic injury of rats after partial hepatectomy. However, the precise mechanisms remain largely unknown. In this study, we examined the effects of PGE1, SST and the combination of these two drugs on acute liver damage of rats after 90% hepatectomy. We found that animal survival was improved when pretreated with PGE1 and SST. Portal venous pressure (PVP), serum alanine aminotransferase (ALT) and aspartate aminotransaminase (AST), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were all reduced after administration of PGE1 and SST. In addition, apoptosis was inhibited via upregulation of Bcl-2 and downregulation of Bax and caspase-3 in drug treatment groups. Furthermore, pretreatment with PGE1 and SST alleviated endoplasmic reticulum (ER) stress by induction of heat shock protein 70 (HSP70) and glucose-regulated protein 78 (GRP78), but suppression of transcription factor C/EBP homologous protein (CHOP). Our data suggest that administration of PGE1 and SST, particularly in combination, may prevent acute liver damage of rats after massive hepatectomy by inhibiting inflammatory responses, apoptosis and ER stress.

Extended liver resection leads to hepatic failure because of a small remnant liver volume. Excessive parenchymal damage has been proposed as the principal cause of this failure, but little is known about the contribution of a primary deficiency in liver regeneration. We developed a mouse model to assess the regenerative capacity of a critically small liver remnant.

Extended (86%) hepatectomy (eHx) was modified to minimize collateral damage; effects were compared with those of standard (68%) partial hepatectomy (pHx) in mice. Markers of liver integrity and survival were evaluated after resection. Liver regeneration was assessed by weight gain, proliferative activity (analyses of Ki67, proliferating cell nuclear antigen, phosphorylated histone 3, mitosis, and ploidy), and regeneration-associated molecules. Knockout mice were used to study the role of p21.

Compared with pHx, survival of mice was reduced after eHx, and associated with cholestasis and impaired liver function. However, no significant differences in hepatocyte death, sinusoidal injury, oxidative stress, or energy depletion were observed between mice after eHx or pHx. No defect in the initiation of hepatocyte proliferation was apparent. However, restoration of liver mass was delayed after eHx and associated with inadequate induction of Foxm1b and a p21-dependent delay in cell-cycle progression. In p21(-/-) mice, the cell cycle was restored, the gain in liver weight was accelerated, and survival improved after eHx.

Significant parenchymal injury is not required for liver failure to develop after extended hepatectomy. Rather, liver dysfunction after eHx results from a transient, p21-dependent block before hepatocyte division. Therefore, a deficiency in cell-cycle progression causes liver failure after extended hepatectomy and can be overcome by inhibition of p21.

Mechanisms concerning life or death decisions in protozoan parasites are still imperfectly understood. Comparison with higher eukaryotes has led to the hypothesis that caspase-like enzymes could be involved in death pathways. This hypothesis was reinforced by the description of caspase-related sequences in the genome of several parasites, including Plasmodium, Trypanosoma and Leishmania. Although several teams are working to decipher the exact role of metacaspases in protozoan parasites, partial, conflicting or negative results have been obtained with respect to the relationship between protozoan metacaspases and cell death. The aim of this paper is to review current knowledge of protozoan parasite metacaspases within a drug targeting perspective.

The only currently offered curative option for many patients with primary or secondary liver tumors is the resection of hepatic tumors. The aim of this study was to evaluate the role of recombinant human erythropoietin (rhEPO) in liver protection and regeneration after subtotal hepatectomy in rats. Rats undergoing 70% hepatectomy received an intraperitoneal injection of saline (control) or rhEPO (4 U/g) 30 minutes prior to resection. Liver function was assessed by the measurement of the international normalized ratio (INR) levels, and hepatic injury was assessed by serum alanine aminotransferase and aspartate aminotransferase levels. Hepatic apoptosis was assessed by intrahepatic caspase-3 activity and morphological criteria. The regeneration capacity of remnant livers was assessed over 7 days with the regenerated liver/body weight ratio, immunohistochemistry markers of cell proliferation (Ki-67) and angiogenesis (von Willebrand factor), and phosphorylated extracellular signal-regulated kinase signaling. Two and 4 days after subtotal hepatectomy, the regenerated liver/body weight ratio was significantly higher in animals treated with rhEPO versus the control group (P < 0.005). Serum liver enzymes and INR levels on days 2 and 4 post-hepatectomy were significantly lower in animals pretreated with rhEPO in comparison with the control group (P < 0.005). No statistically significant difference was noted in intrahepatic hepatic caspase-3 activity, immunohistochemistry for caspase-3, or a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay between the hepatectomized groups. In the rhEPO-pretreated group, the mitotic index, Ki-67 and von Willebrand factor expression, and extracellular signal-regulated kinase activity were significantly higher on day 2 post-hepatectomy (P < 0.05) in comparison with the control group. In conclusion, rhEPO treatment may offer a unique beneficial dual-function strategy for hepatic protection and regeneration immediately after subtotal hepatectomy in rats.

Decreasing hepatocyte injury and death is an attractive therapeutic target in chronic hepatitis C and other liver diseases. Apoptotic cell death is a critical mechanism responsible for liver injury in hepatitis C, and contributes to hepatic fibrogenesis. At the cellular level, apoptosis is executed by a family of cysteine proteases termed caspases. Caspase inhibitors have been developed to inhibit these proteases and attenuate cellular apoptosis in vivo. By reducing hepatocyte apoptosis these agents have the potential to serve as hepatoprotective agents, minimizing liver injury and fibrosis. Studies on a variety of animal models, and time-limited studies in human patients with hepatitis C suggest these are promising therapeutic agents. However, although these agents hold promise, their usefulness requires further studies, especially longer duration studies using hepatic fibrogenesis as the end point before they can be considered further for the treatment of patients infected with the hepatitis C virus.

The pro-inflammatory cytokine IL-18 and its activator Caspase-1 are involved in acute liver failure and acute-on-chronic-liver-failure. In acute liver failure and acute-on-chronic-liver-failure, the MARS system has been used to support liver function. Enhancement of IL-18, as seen in other extracorporeal-support systems like hemodialysis might thus have mitigated beneficial effects of the MARS system in acute hepatic failure.

We measured serum concentrations of IL-18 and Caspase-1 in 10 patients with acute liver failure and 10 patients suffering from acute-on-chronic-liver-failure, who were all treated with MARS. Thirteen patients suffering from chronic hepatic failure and 15 healthy individuals served as controls. Data are given as mean with 95% CI.

Baseline IL-18 serum concentrations were significantly increased in acute liver failure and acute-on-chronic-liver-failure patients as compared to chronic hepatic failure (P=0.0039 and P=0.0011, respectively) and controls (P=0.0028 and P=0.0014, respectively). Caspase-1 serum concentrations were as well significantly elevated in the acute liver failure and acute-on-chronic-liver-failure groups as compared to chronic hepatic failure patients (P=0.0039 and P=0.0232, respectively) and controls P<0.0001 and P<0.0007, respectively). IL-18 and Caspase-1 did not change significantly during MARS treatment in acute liver failure and acute-on-chronic-liver-failure patients.

MARS had no effect on IL-18 and Caspase-1 serum concentrations in acute liver failure and acute-on-chronic-liver-failure, providing no evidence of harmful effects by the increase of these potentially hepatocidal cytokines.