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9 Publications visible to you, out of a total of 9
Influence of Liver Fibrosis on Lobular Zonation

Abstract (Expand)

Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl4 administration for 2, 6 and 12 months to … induce pericentral damage, as well as bile duct ligation (21 days) and mdr2−/− mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl4; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated ‘periportalization’ was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds.

Authors: Ahmed Ghallab, Maiju Myllys, Christian Holland, Ayham Zaza, Walaa Murad, Reham Hassan, Yasser A Ahmed, Tahany Abbas, Eman Abdelrahim, Kai Markus Schneider, Madlen Matz-Soja, Joerg Reinders, Rolf Gebhardt, Theresa Hildegard Wirtz, Maximilian Hatting, Dirk Drasdo, Julio Saez-Rodriguez, Christian Trautwein, Jan Hengstler

Date Published: 1st Dec 2019

Publication Type: Not specified

Bile micro-infarcts in cholestasis are initiated by rupture of the apical hepatocyte membrane and cause shunting of bile to sinusoidal blood

Abstract

Not specified

Authors: Ahmed Ghallab, Ute Hofmann, Selahaddin Sezgin, Nachiket Vartak, Reham Hassan, Ayham Zaza, Patricio Godoy, Kai Markus Schneider, Georgia Guenther, Yasser A Ahmed, Aya A Abbas, Verena Keitel, Lars Kuepfer, Steven Dooley, Frank Lammert, Christian Trautwein, Michael Spiteller, Dirk Drasdo, Alan F Hofmann, Peter L M Jansen, Jan G Hengstler, Raymond Reif

Date Published: 13th Aug 2018

Publication Type: Not specified

Spatio-temporal visualization of the distribution of acetaminophen as well as its metabolites and adducts in mouse livers by MALDI MSI

Abstract (Expand)

Acetaminophen (APAP) is one of the most intensively studied compounds that causes hepatotoxicity in the pericentral region of the liver lobules. However, spatio-temporal information on the distribution … of APAP, its metabolites and GSH adducts in the liver tissue is not yet available. Here, we addressed the question, whether APAP-GSH adducts and GSH depletion show a zonated pattern and whether the distribution of APAP and its glucuronide as well as sulfate conjugates in liver lobules are zonated. For this purpose, a matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) technique was established, where the MSI images were superimposed onto CYP2E1 immunostained tissue. A time-dependent analysis (5, 15, 30, 60, 120, 240, 480 min) after intraperitoneal administration of 300 mg/kg APAP and a dose-dependent analysis (56 up to 500 mg APAP/kg) at 30 min were performed. The results demonstrate that the MALDI MSI technique allows the assignment of compounds and their metabolites to specific lobular zones. APAP-GSH adducts and GSH depletion occurred predominantly in the CYP2E1-positive zone of the liver, although GSH also decreased in the periportal region. In contrast, the parent compound, APAP sulfate and APAP glucuronide did not show a zonated pattern and tissue concentrations showed a similar time course as the corresponding analyses were performed with blood from the portal and liver veins. In conclusion, the present study is in agreement with the concept that pericentral CYPs form NAPQI that in the same cell binds to and depletes GSH but a lower level of GSH adducts is also observed in the periportal region. The results also provide further evidence of the recently published concept of 'aggravated loss of clearance capacity' according to which also liver tissue that survives intoxication may transiently show decreased metabolic capacity.

Authors: Selahaddin Sezgin, Reham Hassan, Sebastian Zühlke, Lars Kuepfer, Jan G. Hengstler, Michael Spiteller, Ahmed Ghallab

Date Published: 23rd Jul 2018

Publication Type: Not specified

Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage

Abstract

Not specified

Authors: Arne Schenk, Ahmed Ghallab, Ute Hofmann, Reham Hassan, Michael Schwarz, Andreas Schuppert, Lars Ole Schwen, Albert Braeuning, Donato Teutonico, Jan G. Hengstler, Lars Kuepfer

Date Published: 1st Dec 2017

Publication Type: Not specified

Adverse outcome pathways: opportunities, limitations and open questions.

Abstract (Expand)

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory … purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.

Authors: M. Leist, A. Ghallab, R. Graepel, R. Marchan, R. Hassan, S. H. Bennekou, A. Limonciel, M. Vinken, S. Schildknecht, T. Waldmann, E. Danen, B. van Ravenzwaay, H. Kamp, I. Gardner, P. Godoy, F. Y. Bois, A. Braeuning, R. Reif, F. Oesch, D. Drasdo, S. Hohme, M. Schwarz, T. Hartung, T. Braunbeck, J. Beltman, H. Vrieling, F. Sanz, A. Forsby, D. Gadaleta, C. Fisher, J. Kelm, D. Fluri, G. Ecker, B. Zdrazil, A. Terron, P. Jennings, B. van der Burg, S. Dooley, A. H. Meijer, E. Willighagen, M. Martens, C. Evelo, E. Mombelli, O. Taboureau, A. Mantovani, B. Hardy, B. Koch, S. Escher, C. van Thriel, C. Cadenas, D. Kroese, B. van de Water, J. G. Hengstler

Date Published: 19th Oct 2017

Publication Type: Not specified

Towards knowledge-driven cross-species extrapolation

Abstract

Not specified

Authors: Christoph Thiel, Ute Hofmann, Ahmed Ghallab, Rolf Gebhardt, Jan G. Hengstler, Lars Kuepfer

Date Published: 1st Apr 2017

Publication Type: Not specified

In vivo imaging of systemic transport and elimination of xenobiotics and endogenous molecules in mice

Abstract (Expand)

We describe a two-photon microscopy-based method to evaluate the in vivo systemic transport of compounds. This method comprises imaging of the intact liver, kidney and intestine, the main organs …gans responsible for uptake and elimination of xenobiotics and endogenous molecules. The image quality of the acquired movies was sufficient to distinguish subcellular structures like organelles and vesicles. Quantification of the movement of fluorescent dextran and fluorescent cholic acid derivatives in different organs and their sub-compartments over time revealed significant dynamic differences. Calculated half-lives were similar in the capillaries of all investigated organs but differed in the specific sub-compartments, such as parenchymal cells and bile canaliculi of the liver, glomeruli, proximal and distal tubules of the kidney and lymph vessels (lacteals) of the small intestine. Moreover, tools to image immune cells, which can influence transport processes in inflamed tissues, are described. This powerful approach provides new possibilities for the analysis of compound transport in multiple organs and can support physiologically based pharmacokinetic modeling, in order to obtain more precise predictions at the whole body scale.

Authors: Raymond Reif, Ahmed Ghallab, Lynette Beattie, Georgia Günther, Lars Kuepfer, Paul M. Kaye, Jan G. Hengstler

Date Published: 1st Mar 2017

Publication Type: Not specified

The ascending pathophysiology of cholestatic liver disease

Abstract (Expand)

In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending … course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738).

Authors: Peter L.M. Jansen, Ahmed Ghallab, Nachiket Vartak, Raymond Reif, Frank G. Schaap, Jochen Hampe, Jan G. Hengstler

Date Published: 1st Feb 2017

Publication Type: Not specified

Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases

Abstract (Expand)

BACKGROUND & AIMS: Recently, spatial-temporal/metabolic mathematical models have been established that allow the simulation of metabolic processes in tissues. We applied these models to decipher …er ammonia detoxification mechanisms in the liver. METHODS: An integrated metabolic-spatial-temporal model was used to generate hypotheses of ammonia metabolism. Predicted mechanisms were validated using time-resolved analyses of nitrogen metabolism, activity analyses, immunostaining and gene expression after induction of liver damage in mice. Moreover, blood from the portal vein, liver vein and mixed venous blood was analyzed in a time dependent manner. RESULTS: Modeling revealed an underestimation of ammonia consumption after liver damage when only the currently established mechanisms of ammonia detoxification were simulated. By iterative cycles of modeling and experiments, the reductive amidation of alpha-ketoglutarate (α-KG) via glutamate dehydrogenase (GDH) was identified as the lacking component. GDH is released from damaged hepatocytes into the blood where it consumes ammonia to generate glutamate, thereby providing systemic protection against hyperammonemia. This mechanism was exploited therapeutically in a mouse model of hyperammonemia by injecting GDH together with optimized doses of cofactors. Intravenous injection of GDH (720 U/kg), α-KG (280 mg/kg) and NADPH (180 mg/kg) reduced the elevated blood ammonia concentrations (>200 μM) to levels close to normal within only 15 min. CONCLUSION: If successfully translated to patients the GDH-based therapy might provide a less aggressive therapeutic alternative for patients with severe hyperammonemia.

Authors: Ahmed Ghallab, Géraldine Cellière, Sebastian G. Henkel, Dominik Driesch, Stefan Hoehme, Ute Hofmann, Sebastian Zellmer, Patricio Godoy, Agapios Sachinidis, Meinolf Blaszkewicz, Raymond Reif, Rosemarie Marchan, Lars Kuepfer, Dieter Häussinger, Dirk Drasdo, Rolf Gebhardt, Jan G. Hengstler

Date Published: 1st Apr 2016

Publication Type: Not specified

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