Cyclooxygenase-2 contributes to the selective induction of cell death by the endocannabinoid 2-arachidonoyl glycerol in hepatic stellate cells.

The endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) is an anti-fibrotic lipid mediator that induces apoptosis in hepatic stellate cells (HSCs), but not in hepatocytes. However, the exact molecular mechanisms of this selective induction of HSC death are still unresolved. Interestingly, the inducible isoform of cyclooxygenase, COX-2, can metabolize 2-AG to pro-apoptotic prostaglandin glycerol esters (PG-GEs). We analyzed the roles of COX-2 and endocannabinoid-derived PG-GEs in the differential susceptibility of primary activated HSCs and hepatocytes toward 2-AG-induced cell death. HSCs displayed significant COX-2 expression in contrast to hepatocytes. Similar to 2-AG, treatment of HSCs with PGD2-GE dose-dependently induced cell death independently from cannabinoid receptors that was accompanied by PARP- and caspase 3-cleavage. In contrast to 2-AG, PGD2-GE failed to induce significant ROS formation in HSCs, and depletion of membrane cholesterol did not rescue HSCs from PGD2-GE-induced apoptosis. These findings indicate differential engagement of initial intracellular signaling pathways by 2-AG and its COX-2-derived metabolite PGD2-GE, but similar final cell death pathways. Other PG-GEs, such as PGE2-or PGF2α-GE did not induce apoptosis in HSCs. Primary rat hepatocytes were mainly resistant against 2-AG- and PGD2-GE-induced apoptosis. HSCs, but not hepatocytes were able to metabolize 2-AG to PGD2-GE. As a proof of principle, HSCs from COX-2(-/-) mice lacked PDG2-GE production after 2-AG treatment. Accordingly, COX-2(-/-) HSCs were resistant against 2-AG-induced apoptosis. In conclusion, the divergent expression of COX-2 in HSCs and hepatocytes contributes to the different susceptibility of these cell types towards 2-AG-induced cell death due to the generation of pro-apoptotic PGD2-GE by COX-2 in HSCs. Modulation of COX-2-driven metabolization of 2-AG may provide a novel physiological concept allowing the specific targeting of HSCs in liver fibrosis.

Role of the endocannabinoid system in alcoholic liver disease.

Alcohol abuse is a major cause of liver fibrosis and cirrhosis in developed countries. Alcoholic liver disease (ALD) is distinctively characterized by a pronounced inflammatory response due to elevated gut-derived endotoxin plasma levels, an augmented generation of oxidative stress with pericentral hepatic hypoxia and the formation of noxious ethanol metabolites (e.g. acetaldehyde or lipid oxidation products). These factors, based on a complex network of cytokine actions, together result in increased hepatocellular damage and activation of hepatic stellate cells, the key cell type of liver fibrogenesis. Recent studies suggest that the endocannabinoid system is a signaling system that also plays an important role in the pathogenesis of ALD. A study comparing chronic alcohol administration in cannabinoid receptor (CB) 1 or CB2 knockout versus wild-type mice revealed that CB1 signaling aggravated hepatic steatosis and fibrogenesis whereas CB2 protected the liver from ALD. These data suggested a protective role of CB2 (in contrast to CB1) in ALD. Similar results were found in global or hepatocyte-specific CB1 knockout mice that were resistant to ethanol-induced steatosis. Moreover, ethanol feeding upregulated the endocannabinoid 2-arachidonoyl glycerol and its biosynthetic enzyme diacylglycerol lipase-ß selectively in hepatic stellate cells and subsequently increased expression of CB1 receptors in hepatocytes of wild-type mice leading to CB1-dependent hepatic steatosis by activation of lipogenic pathways. This ethanol-induced upregulation of CB1 receptors was partly dependent on the ethanol metabolite acetaldehyde. Thus, the hepatic endocannabinoid system offers emerging options for therapeutic exploitation not only for liver disease in general, but also for ALD.

[The problems of compliance and adherence, using the example of chronic inflammatory bowel disease]. / Das Problem von Compliance und Adhärenz am Beispiel der chronisch entzündlichen Darmerkrankungen.

To what extent do patients comply with their doctor's treatment recommendation, i.e. show "compliance" and "adherence" ?. The treatment of chronic diseases in particular is associated with enormous problems of adherence. Patients often take only 40 to 80% of their prescribed dosage of medication. This issue affects not only the course of the disease in the particular patient, but also has considerable impact on the health care system. Great difficulties still exist in recognizing poor adherence, because doctors depend on the information given by their patients. The reasons for adherence problems can be attributed to disease-related, treatment-related or patient-related factors, as well as to the quality of the doctor-patient relationship. Improving adherence is difficult due to its numerous and individually different causes. This has been emphasized by a recent Cochrane review, in which only 5 out of 21 randomized and controlled studies concerning the improvement of adherence demonstrated significant success. However, half of the studies displayed methodological errors that weakened the statistical detection of improvement because of the low numbers patients. Overall, enormous efforts will be required of doctors, patients and health care policies to achieve substantial alterations in the problems associated with adherence.

[Effects of alcohol on the upper gastrointestinal tract and the pancreas--an up-to-date overview]. / Wirkungen von Alkohol auf den oberen Gastrointestinaltrakt und das Pankreas--Eine aktuelle Ubersicht.

The oesophagus, stomach and pancreas are primary target organs for ethanol-related diseases. In the oesophagus and stomach, ethanol induces motility disorders and mucosal lesions that are dose-dependent and reversible under acute conditions. Chronic consumption of alcohol causes a significant increase in the risk for squamous carcinoma of the oesophagus. All of these effects are mainly caused by direct contact of alcohol or its metabolite acetaldehyde with the mucosa. Non-alcoholic components are responsible for many effects of alcoholic beverages, including the powerful stimulation of gastric acid secretion by beverages that are produced by fermentation. In the exocrine pancreas, alcohol induces secretory alterations that are mainly affected by the manner and duration of alcohol exposure, the additional administration of food, the type of beverage or the basal secretory state of the gland. Because the pancreas is not topically exposed to ethanol, these ethanol effects on pancreatic secretion are primarily caused by systemic cholinergic mechanisms of the vagus nerve. Chronic alcohol abuse may cause chronic alcoholic pancreatitis after recurrent subclinical inflammatory episodes. Genetic predispositions are believed to play an additional role in the pathomechanism of the disease. In contrast to the cardiovascular system, moderate consumption of alcoholic beverages does not have any beneficial health effects on the oesophagus, stomach or pancreas. Future research needs to define the exact molecular mechanisms and the role of different genetic predispositions for alcohol-induced diseases as well as the effects of the non-alcoholic components of alcoholic beverages.