PloS one, 2016-06, Vol.11 (6), p.e0158156
2016
Details
- Autor(en) / Beteiligte
- Titel
- Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis
- Ist Teil von
- PloS one, 2016-06, Vol.11 (6), p.e0158156
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Interactions between C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) and their ligands, including CCL2 and CCL5, mediate fibrogenesis by promoting monocyte/macrophage recruitment and tissue infiltration, as well as hepatic stellate cell activation. Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. CVC's anti-inflammatory and antifibrotic effects were evaluated in a range of preclinical models of inflammation and fibrosis. Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC's antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alcoholic steatohepatitis (NASH) and renal fibrosis. Study assessments included body and liver/kidney weight, liver function test, liver/kidney morphology and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses. CVC significantly reduced monocyte/macrophage recruitment in vivo at doses ≥20 mg/kg/day (p < 0.05). At these doses, CVC showed antifibrotic effects, with significant reductions in collagen deposition (p < 0.05), and collagen type 1 protein and mRNA expression across the three animal models of fibrosis. In the NASH model, CVC significantly reduced the non-alcoholic fatty liver disease activity score (p < 0.05 vs. controls). CVC treatment had no notable effect on body or liver/kidney weight. CVC displayed potent anti-inflammatory and antifibrotic activity in a range of animal fibrosis models, supporting human testing for fibrotic diseases. Further experimental studies are needed to clarify the underlying mechanisms of CVC's antifibrotic effects. A Phase 2b study in adults with NASH and liver fibrosis is fully enrolled (CENTAUR Study 652-2-203; NCT02217475).
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0158156Titel-ID: cdi_plos_journals_1799848286
- Format
- –
- Schlagworte
- Acquired immune deficiency syndrome, Adults, AIDS, Analysis, Animal models, Animals, Biology and Life Sciences, CC chemokine receptors, CCR2 protein, CCR5 protein, CCR5 Receptor Antagonists - administration & dosage, CCR5 Receptor Antagonists - pharmacology, CCR5 Receptor Antagonists - therapeutic use, Cell activation, Chemokine receptors, Chemokines, Chemotaxis, Collagen, Collagen (type I), Collagens, Cytokines, Deposition, Disease control, Drug dosages, Drug therapy, Fatty liver, FDA approval, Fibrosis, Gastroenterology, Gene expression, Hepatology, Imidazoles - administration & dosage, Imidazoles - pharmacology, Imidazoles - therapeutic use, In vivo methods and tests, Infiltration, Inflammation, Insulin resistance, Kidney Diseases - drug therapy, Kidney Diseases - pathology, Kidneys, Ligands, Liver, Liver diseases, Macrophages, Macrophages - drug effects, Male, Medicine, Medicine and Health Sciences, Mice, Mice, Inbred C57BL, Monocyte chemoattractant protein 1, Monocytes, Monocytes - drug effects, Non-alcoholic Fatty Liver Disease - drug therapy, Non-alcoholic Fatty Liver Disease - pathology, Peritonitis, Pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Receptors, CCR2 - antagonists & inhibitors, Recruitment, Research and Analysis Methods, Risk factors, Rodents, Sulfoxides, Thioacetamide