Abstract
staining and smooth muscle alpha actin immunolabeling, and decreased expression of fibrogenic genes in treated vs untreated animals. Moreover, JZL184 significantly decreased the influx of Ly6C+ infiltrating monocytes into the liver of CCl4-exposed mice. Accordingly, JZL 184 reduced the hepatic expression of Ly6C mRNA and decreased the hepatic expression of IL1-b, CCL2, CCL4 and CCL5 mRNAs. In vitro studies demonstrated that JZL184 (i) reduced hepatic myofibroblast proliferation; (ii) down-regulated LPS-stimulation of inflammatory mediator expression (IL1-b, CCL2, CCL4 and CCL5 mRNAs) from peritoneal macrophages. Finally, MAGL mRNA expression was increased in PBMC from patients with alcoholic cirrhosis as compared to healthy subjects and further enhanced in LPS-exposed PBMC. Conclusions: Pharmacological inhibition of MAGL accelerates liver fibrosis regression in a model of toxin-induced liver injury, most probably by a mechanism involving reduction of infiltrating pro-inflammatory monocytes into the liver and a decrease in inflammatory mediators produced by macrophages. These results unravel MAGL inhibition as a novel promising antifibrogenic approach.
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