title: Opioid-like compound exerts anti-fibrotic activity via decreased hepatic stellate cell activation and inflammation.
abstract: Hepatic fibrosis is characterized by excess type I collagen deposition and exacerbated inflammatory response. Naltrexone, an opioid receptor antagonist used for treating alcohol abuse, attenuates hepatocellular injury in fibrotic animal models, which can be accompanied by deleterious side effects. Additionally, opioid neurotransmission is upregulated in patients with inflammatory liver disease. Several derivatives of Naltrexone, Nalmefene (Nal) and JKB-119, exert immunomodulatory activity; however, unlike Nal, JKB-119 does not show significant opioid receptor antagonism. To delineate the potential hepatoprotective effects of these compounds, we investigated if JKB-119 and Nal could modulate activation of hepatic stellate cells (HSCs), primary effector cells that secrete type I collagen and inflammatory mediators during liver injury. Our results demonstrated that Nal or JKB-119 treatment decreased smooth muscle α-actin, a marker of HSC activation, mRNA and protein expression. Despite decreased collagen mRNA expression, both compounds increased intracellular collagen protein expression; however, inhibition of collagen secretion was observed. To address a possible mechanism for suppressed collagen secretion or retention of intracellular collagen, endoplasmic (ER) protein expression and matrix metalloproteinase (MMP) activity were examined. While no change in ER protein expression (Grp78, PDI, Hsp47) was observed, MMP13 mRNA expression was dramatically increased. In an acute LPS inflammatory injury animal model, JKB-119 treatment decreased liver injury (ALT), plasma TNFα and PMN liver infiltration. Overall, these results suggest that JKB-119 can directly inhibit HSC activation attributed to anti-inflammatory activity and may, therefore, attenuate inflammation associated with HSC activation and liver disease.
authors.affiliation: Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
authors.forename: Stephani A
authors.initials: SA
authors.lastname: Day
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Lakner
authors.forename: Cathy C
authors.initials: CC
authors.lastname: Moore
authors.forename: Mao-Hsiung
authors.initials: MH
authors.lastname: Yen
authors.forename: Mark G
authors.initials: MG
authors.lastname: Clemens
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Wu
authors.forename: Laura W
authors.initials: LW
authors.lastname: Schrum
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D009019:Morphinans / Q000494:pharmacology* / Q000627:therapeutic use; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003094:Collagen; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2; D009019:Morphinans; D009271:Naltrexone; D009292:Narcotic Antagonists; C558394:JKB 119; C498862:Acta2 protein, rat; C507083:Mmp13 protein, rat; C522363:Mmp2 protein, rat; C038981:nalmefene