title: Upregulation of cannabinoid receptor-1 and fibrotic activation of mouse hepatic stellate cells during Schistosoma J. infection: role of NADPH oxidase.
abstract: The endocannabinoid system (CS) has been implicated in the development of hepatic fibrosis such as schistosomiasis-associated liver fibrosis (SSLF). However, the mechanisms mediating the action of the CS in hepatic fibrosis are unclear. The present study hypothesized that Schistosoma J. infection upregulates cannabinoid receptor 1 (CB1) due to activation of NADPH oxidase leading to a fibrotic phenotype in hepatic stellate cells (HSCs). The SSLF model was developed by infecting mice with Schistosoma J. cercariae in the skin, and HSCs from control and infected mice were then isolated, cultured, and confirmed by analysis of HSC markers α-SMA and desmin. CB1 significantly increased in HSCs isolated from mice with SSLF, which was accompanied by a greater expression of fibrotic markers α-SMA, collagen I, and TIMP-1. CB1 upregulation and enhanced fibrotic changes were also observed in normal HSCs treated with soluble egg antigen (SEA) from Schistosoma J. Electron spin resonance (ESR) analysis further demonstrated that superoxide (O2(-)) production was increased in infected HSCs or normal HSCs stimulated with SEA. Both Nox4 and Nox1 siRNA prevented SEA-induced upregulation of CB1, α-SMA, collagen I, and TIMP-1 by inhibition of O2(-) production, while CB1 siRNA blocked SEA-induced fibrotic changes without effect on O2(-) production in these HSCs. Taken together, these data suggest that the fibrotic activation of HSCs on Schistosoma J. infection or SEA stimulation is associated with NADPH oxidase-mediated redox regulation of CB1 expression, which may be a triggering mechanism for SSLF.
authors.affiliation: Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie-Fang Avenue, Wuhan 430030, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Justine M
authors.initials: JM
authors.lastname: Abais
authors.affiliation: Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie-Fang Avenue, Wuhan 430030, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Meng
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Ritter
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Pin-Lan
authors.initials: PL
authors.lastname: Li
authors.affiliation: Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie-Fang Avenue, Wuhan 430030, China. Electronic address: tangwx@tjh.tjmu.edu.cn.
authors.forename: Wang-Xian
authors.initials: WX
authors.lastname: Tang
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000947:Antigens, Helminth / Q000302:isolation & purification / Q000494:pharmacology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D006790:Host-Parasite Interactions; D008099:Liver / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000235:genetics* / Q000469:parasitology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012549:Schistosoma japonicum / Q000502:physiology; D012554:Schistosomiasis japonica / Q000150:complications / Q000235:genetics* / Q000469:parasitology / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D000947:Antigens, Helminth; D024042:Collagen Type I; D003893:Desmin; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D043884:Receptor, Cannabinoid, CB1; D019715:Tissue Inhibitor of Metalloproteinase-1; C544013:alpha-smooth muscle actin, mouse; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C422943:Nox4 protein, mouse
keywords: Cannabinoid receptor-1; Hepatic stellate cell; NADPH oxidase; Schistosomiasis-associated liver fibrosis