Recent studies have implicated dysregulation of the endocannabinoid system in various liver diseases and their complications (e.g., hepatitis, fibrosis, cirrhosis, cirrhotic cardiomyopathy, and ischemia-reper-fusion), and demonstrated that its modulation by either cannabinoid 2 (CB2) receptor agonists or CB1 antagonists may be of significant therapeutic benefits. This review is aimed to focus on the triggers and sources of endocannabinoids during liver inflammation and on the novel role of CB2 receptors in the interplay between the activated endothelium and various inflammatory cells (leukocytes, lymphocytes, etc.), which play pivotal role in the early development and progression of inflammatory and other liver diseases.
Keywords: ischemia-reperfusion, endocannabinoids, cannabinoid 2 receptor, inflammation, endothelium
Conclusions and Future Directions?Collectively, the studies discussed above emphasize the potential immunoregulatory role of the endocannabinoid system in a variety of inflammatory liver disorders, opening new avenues for their pharmacotherapy. There is considerable interest in the development of selective CB2 receptor agonists, which are devoid of psychoactive properties of CB1 agonists, for various inflammatory disorders. Selective CB2 cannabinoid agonists may protect against hepatic inflammatory disorders by attenuating the endothelial cell activation/inflammatory response (e.g., the expression of adhesion molecules, release of chemotactic factors, inflammatory mediators, etc.) and by decreasing the migration and the adhesion of inflammatory cells to the endothelium, transendothelial migration, adhesion to parenchymal cells and activation, and interrelated oxidativenitrosative stress-inflammatory response (Fig. 1).
It appears that CB1 antagonists might be?beneficial in slowing the progression of liver fibrosis and the neurological decline associated with hepatic encephalopathy, in addition to the attenuation of the adverse hemodynamic consequences of cirrhosis, thus extending life until a suitable liver becomes available for transplantation (overviewed in Ref. 26 and by Drs. Gaskari and Lee in this Themes series). CB1 antagonists may also be useful in the treatment of obesity-associated liver diseases and related features of metabolic syndrome by improving dyslipidemia and attenuating systemic and liver inflammation (overviewed by Dr. Kunos in this Themes series).
Despite the clear evidence (reviewed above) indicating that the endocannabinoid system plays an important role in modulating inflammatory response in a variety of liver disorders, the exact mechanisms remain largely elusive. For example, liver contains a large number of immune cells representing the innate immune system (e.g., NK cells, NKT cells, γ/δ T cells, and Kupffer cells), which play a key role not only in the host defenses against invading microorganisms and tumor formation, but also in the pathogenesis of various inflammatory liver diseases (6). Further studies should determine how the endocannabinoid system interacts with these immune cells to design better therapeutic approaches for the treatment of inflammatory liver diseases based on CB1/CB2 agonists or antagonists or their combinations.
Complete study with charts
Endocannabinoids & Liver Disease.III: Endocannabinoid Effects on Immune Cells : Implication for Inflammatory Liver Disease
January 2008 Special Issue British Journal of Pharmacology