Apoptosis In Liver Disease Research Articles

Targeting apoptosis in autoimmune hepatitis.

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.

Mechanisms and biomarkers of apoptosis in liver disease and fibrosis.

Liver fibrosis and cirrhosis are a major cause of morbidity and mortality worldwide. Development of the fibrotic scar is an outcome of chronic liver diseases of varying aetiologies including alcoholic liver disease (ALD) nonalcoholic liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH) viral hepatitis B and C (HBV, HCV). The critical step in the development of scar is activation of hepatic stellate cells (HSCs), which become the primary source of extracellular matrix. Aberrant apoptosis is a feature of chronic liver diseases and is associated with worsening stages of fibrosis. However, apoptosis is also the main mechanism promoting the resolution of fibrosis, and spontaneous or targeted apoptosis of HSC is associated with regression of fibrosis in animal models and patients with chronic liver disease. Given the importance of apoptosis in disease progression and resolution, there is much interest in precisely delineating the mechanisms involved and also developing biomarkers that accurately reflect the underlying pathogenesis. Here, we review the mechanisms driving apoptosis in development of liver disease and use of apoptosis -related biomarkers to aid in clinical diagnosis. Finally, we will also examine the recent literature regarding new insights into mechanisms involved in apoptosis of activated HSCs as possible method of fibrosis regression.

Apoptosis in the liver: a matter of ion fluxes and oxidative stress: Third International Conference of the Collaborative Research Center ‘Experimental Hepatology’ (SFB‐575), Düsseldorf, Germany, 13–14 October 2006

The cell death of hepatocytes is a characteristic feature of liver damage triggered by viral infection, drug abuse, fat overload or autoimmunity. Apoptosis is currently the best-understood form of cell death; however, the precise mechanisms leading to apoptosis in liver disease are largely unknown. Several cellular processes including alterations in cell hydration and ion homeostasis, osmotic and oxidative stress, lysosomal permeabilization as well as alternate forms of cell death may contribute to liver damage. The intriguing complexity and relevance of these processes for liver failure were addressed at the Third International Conference of the Collaborative Research Center 'Experimental Hepatology' (SFB-575),which was held in Düsseldorf, Germany, in 13-14 October 2006. The aim of this symposium was to bring together leading researchers studying cell death pathways in the liver and other systems and to share ideas and recent research findings. This report covers some of the salient and stimulating contributions of the meeting and gives an updated survey of the advances in this burgeoning field of translational medicine.

Apoptosis in liver disease

The description of the morphological hallmarks of programmed cell death, apoptosis, in 1972 by Kerr, Wyllie and Currie started a field of research that revolutionized our understanding of cellular proliferation, tissue homeostasis and pathophysiology of many diseases. In the following years, a series of proteins involved in signaling and intracellular death pathways were identified and 30 years later the Noble Prize for physiology and medicine was awarded to S. Brenner, H. R. Horvitz and J. E. Sulston for their discoveries related to describing the mechanisms of cell death (apoptosis). The delineation of the signaling pathways that mediate apoptosis changed the paradigms of understanding in many liver diseases. The most detailed analyzed mode of apoptosis involves a cell surface-based receptor-ligand system. Death receptors are typically members of the tumor necrosis factor-receptor superfamily and comprise an intracellular death domain. Following ligand binding to the receptor, intracellular adapter molecules are recruited to the receptor and subsequently transmit the apoptotic signal. Intracellular organelle-dependent signaling occurs, and effector molecules then augment the receptor-initiated apoptosis process. Cell death and degradation follows the activation of a highly regulated set of cytosolic and nuclear proteases and DNAses. Receptor-independent activation of the apoptotic process can occur as part of the cytotoxicity related to UV radiation, chemotherapeuticals or other DNA-damaging agents through activation of intracellular sensors of cellular integrity, e.g. the tumor suppressor gene p53. In contrast to necrosis, apoptosis is not commonly accompanied by an inflammatory response that causes collateral cell damage. The apoptotic program is highly effective in eliciting cell death and thus must be tightly controlled. This is achieved through continuous integration of pro- and antiapoptotic signals at the individual cell level. Dysregulation of the apoptotic process, resulting in too much or too little cell death, has potentially devastating effects and has been implicated in many forms of liver disease like acute liver failure or hepatocellular carcinoma. This review will focus initially on recent progress in signaling events of hepatocellular apoptosis and subsequently discuss the consequences for the hepatic pathophysiology that involves disarrangement of hepatocellular apoptosis.

Role of circulating soluble CD40 as an apoptotic marker in liver disease.

To measure levels of soluble CD40, a laboratory marker of apoptosis in patients with liver disease, determine its origin, and correlate the findings with disease activity and histology. Laboratory research study with comparison group. Liver Institute, Laboratory of HLA Typing and Histopathology Department, Rabin Medical Center, Israel. One hundred ten patients with liver disease and 20 healthy controls. Serum samples were collected from all patients; in addition, paired hepatic and portal vein samples were collected from 23 patients, and bile samples from 5 patients. Soluble CD40 was measured with an enzyme-linked immunosorbent assay. Apoptotic cells in liver tissue were identified by morphological criteria and quantified with the TUNEL assay. Soluble CD40 concentration was significantly higher in patients with liver disease than controls (mean 112.9 +/- 197.2 pg/ml vs. 24.2 +/- 9.1 pg/ml, p = 0.0001), with highest levels in the chronic viral hepatitis group (mean 131.7 +/- 137.5 pg/ml, p = 0.0001). Levels of sCD40 were correlated with serum creatinine, alkaline phosphatase, alpha-feto protein, and the apoptotic index. In the 23 paired samples, CD40 level was higher in the hepatic vein (mean 74.9 +/- 114.5 pg/ml) than the portal vein (mean 51.6 +/- 67.9 pg/ml); it was highly detectable in bile (mean 115.6 +/- 119.6 pg/ml, p = 0.0123). Untreated patients with chronic viral hepatitis (B and C) had higher levels (mean 106.2 +/- 76.5 pg/ml) than treated patients (mean 59.3 +/- 68.6 pg/ml, p = 0.049). Levels of soluble CD40 increase in different types of liver disease. It probably derives from the liver and is secreted into the bile. Levels correlate with the apoptotic index and are affected by antiviral treatment. Soluble CD40 may serve as a serum marker of apoptosis in liver disease.

Mechanisms of liver injury: an overview.

Liver cirrhosis, an end-result of a wide variety of the liver diseases, is a world wide health problem. Because of its unique organ system, i.e., portal blood supply, bile formation and enterohepatic circulation, drug metabolism system, and sinusoidal lining cells such as Kupffer, endothelial and stellate cells, the liver is a target of a variety of hepatotoxic insults. Current data suggest that hepatocyte apoptosis is an essential feature contributing to liver injury in a wide range of acute and chronic liver diseases. With an improved understanding of the pathophysiological role of apoptosis in liver diseases, we are now entering an era where regulation of liver cell apoptosis is becoming a therapeutic possibility. Inhibition of hepatocyte apoptosis using a variety of different strategies may be therapeutically beneficial in liver injuries, such as alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), viral hepatitis, and cholestatic liver diseases. Considering the link between hepatocyte apoptosis and liver fibrosis, inhibition of hepatocyte apoptosis may also be an anti-fibrotic therapeutic strategy. Moreover, selective induction of apoptosis of activated stellate cells would be a unique approach to induce the resolution the phase of liver fibrosis. These concepts merit further clinical and basic investigation.

Apoptosis in liver disease

A variety of biological functions are regulated through extracellular signals. Amongst the best studied examples is growth control, which is achieved by the regulatory function of growth factors. In recent years it has become apparent that cell death (apoptosis) is controlled in a similar fashion.Apoptosis, firstly a morphologically defined process, is a highly controlled type of cell death that plays a critical role in embryonic development, deletion of autoreactive T-cells and adult tissue homoeostasis. There is increasing evidence that derangement of the apoptotic program is the underlying cause of a series of diseases including liver diseases. The deadly program can be initiated by ligand binding to membrane bound receptors such as CD95 (Fas), which is the most prominent cell death inducing member of the TNF receptor superfamily. The core of the subsequently activated intracellular machinery is formed by a set of proteases, namely caspases. Once activated, they orchestrate the complete destruction of the cellular skeleton leading to the typical apoptotic morphology. This review focuses on the underlying mechanism leading to derangement of the usually highly controlled apoptotic program in different liver diseases.

Detection of elevated caspase activation and early apoptosis in liver diseases

Apoptosis has been implicated in the pathogenesis of many diseases including various forms of liver failure. The apoptotic process is essentially regulated by intracellular proteases, called caspases, which cleave several vital proteins. Despite the rapid elucidation of apoptotic signaling cascades, however, almost no information exists about the activation of caspases in situ. In the present study, a monoclonal antibody was employed which selectively recognized cleavage site-specific fragments of the caspase substrate cytokeratin-18. We demonstrate that this antibody labeled apoptotic hepatocytes in culture and, in addition, could be used to monitor caspase activation in formalin-fixed tissue biopsies. In liver sections of different liver diseases an increased number of early apoptotic cells was detected which were not found in normal tissue. Our data reveal that hepatobiliary diseases are characterized by elevated caspase activation and apoptosis, which can be specifically detected in situ by a cleavage site-specific antibody against cytokeratin-18.

Life or death: the fate of the hepatic stellate cell following hepatic injury.

HepatologyVolume 27, Issue 5 p. 1447-1448 ElsewhereFree Access Life or death: The fate of the hepatic stellate cell following hepatic injury Richard A. Rippe Ph.D., Richard A. Rippe Ph.D. Department of Medicine, Division of Digestive Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NCSearch for more papers by this author Richard A. Rippe Ph.D., Richard A. Rippe Ph.D. Department of Medicine, Division of Digestive Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NCSearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1002/hep.510270539Citations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. REFERENCES 1 Friedman SL. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med 1993; 328: 1828– 1835.MEDLINE 2 Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends in Biochemical Sciences 1997; 22: 299– 306.MEDLINE 3 Hale AJ, Smith CA, Sutherland LC, Stoneman VEA, Longthorne VL, Culhane AC, Williams GT. Apoptosis: molecular regulation of cell death. Eur J Biochem 1996; 236: 1– 26.MEDLINE 4 Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 1998; 391: 43– 50.MEDLINE 5 Galle PR. Apoptosis in liver disease. J Hepatol 1997; 27: 405– 412.MEDLINE 6 Adachi M, Suematsu S, Kondo T, Ogasawara J, Tanaka T, Yoshida N, Nagata S. Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver. Nature Genetics 1995; 11: 294– 300.MEDLINE 7 Jones BA, Gores GJ. Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine. Gastrointest Liver Physiol 36 Am J Physiol 1997; 273: G1174– 1188.MEDLINE 8 Itoh N, Tsujimoto Y, Nagata S. Effect of bcl-2 on Fas antigen-mediated cell death. J Immunol 1993; 151: 621– 627.MEDLINE 9 Evan GI, Brown L, Whyte M, Harrington E. Apoptosis and the cell cycle. Curr Op Cell Biol 1995; 7: 825– 834.MEDLINE 10 Feldmann G. Liver apoptosis. J Hepatol 1997; 26:(suppl 2): 1– 11. Citing Literature Volume27, Issue5May 1998Pages 1447-1448 ReferencesRelatedInformation

Dysregulation of apoptosis as a mechanism of liver disease: an overview.

Apoptosis is a morphologically distinct form of cell death which occurs in a wide variety of liver diseases. In this overview chapter, we review: (1) the current definitions of apoptosis; (2) the biochemical pathways effecting apoptosis; and (3) the intracellular pathways regulating apoptosis. We also describe how apoptosis is identified in the liver and review the ligand/receptor interactions which trigger hepatobiliary apoptosis. Finally, we speculate on potential therapeutic applications for modulating apoptosis in human liver diseases. This information is meant to provide a foundation for the following chapters each focused on a specific role of apoptosis in liver diseases.

Apoptosis in liver disease.

Apoptosis in liver disease.

Role of transforming growth factor beta 1 on hepatic regeneration and apoptosis in liver diseases.

To investigate the effects of transforming growth factor beta 1 (TGF-beta 1) on regeneration and induction of apoptosis of liver cell and bile duct in various liver diseases. Formalin fixed paraffin wax sections of 18 liver tissue samples were obtained by needle biopsy, surgery, or necropsy; these included six liver cirrhosis, three obstructive jaundice; five fulminant hepatitis, one subacute hepatitis, and three normal liver. Expression of TGF-beta 1, apoptosis related Le(y) antigen, Fas antigen, a receptor for tumour necrosis factor, and biotin nick end labelling with terminal deoxynucleotidyl transferase mediated dUTP (TUNEL) for locating DNA fragmentation, was investigated histochemically. TGF-beta 1 was expressed in areas of atypical bile duct proliferation, where bile duct continuously proliferated from liver cells. In occlusive jaundice and fulminant hepatitis, TUNEL was positive in nuclei and cytoplasm of metaplastic cells which formed incomplete bile ducts, and these cells appeared to extend from TGF-beta 1 expressing liver cells. Fas antigen was found only on the cell membrane of proliferated bile duct in fulminant hepatitis, which differed from TGF-beta 1 and TUNEL positive areas. Le(y) antigen was expressed in liver cell and bile duct at the areas with atypical bile duct proliferation, but its coexpression with TUNEL was rare. TGF-beta 1 plays a role in the arrest of liver cell regeneration and atypical bile duct proliferation, and in areas of rapidly progressing atypical bile duct proliferation, such as in fulminant hepatitis or bile retention. Apoptosis appears to be induced by TGF-beta 1. This phenomenon may account for the inadequate hepatic regeneration that occurs with liver disease.