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Pentoxifylline blocks hepatic stellate cell activation independently of phosphodiesterase inhibitory activity

Authors
 KWAN S. LEE  ;  HOWARD B. COTTAM  ;  KARL HOUGLUM  ;  D. BRUCE WASSON  ;  DENNIS CARSON  ;  MARIO CHOJKIER 
Citation
 AMERICAN JOURNAL OF PHYSIOLOGY, Vol.273(5) : 1094-1100, 1997 
Journal Title
 AMERICAN JOURNAL OF PHYSIOLOGY 
ISSN
 0002-9513 
Issue Date
1997
MeSH
3T3 Cells ; Actins/biosynthesis ; Animals ; Carbon Tetrachloride/toxicity ; Cell Division/drug effects ; Cell Nucleus/metabolism ; Collagen/biosynthesis ; Cyclic AMP/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Gene Expression Regulation/drug effects* ; Liver/cytology ; Liver/drug effects* ; Liver/physiology ; Male ; Mice ; NF-kappa B/biosynthesis ; Oxidative Stress ; Pentoxifylline/analogs & derivatives ; Pentoxifylline/pharmacology* ; Phosphodiesterase Inhibitors/pharmacology ; Phosphorylation ; Promoter Regions, Genetic ; Proto-Oncogene Proteins/biosynthesis ; Proto-Oncogene Proteins c-myb ; Rats ; Rats, Sprague-Dawley ; Trans-Activators/biosynthesis
Abstract
Activated, but not quiescent, hepatic stellate cells (lipocytes) have a high level of collagen type I and smooth muscle actin (SMA) gene expression. Therefore, stellate cell activation is a critical step in hepatic fibrosis. The mechanisms leading to stellate cell activation in vivo are unknown. The characteristic hepatic oxidative stress cascade induced in rats by CCl4 markedly stimulated stellate cell entry into S phase, nuclear factor (NF)-kappa B activity, and c-myb expression. These changes were prevented by pentoxifylline, which also decreased CCl4-induced hepatic injury. As expected, cAMP-mediated phosphorylation of CREB-Ser133 was induced in vivo in stellate cells by pentoxifylline but not by its metabolite 5, an N-1 carboxypropyl derivative, which lacks phosphodiesterase inhibitory activity. Stellate cell nuclear extracts from CCl4-treated, but not from control, animals formed a complex with the critical promoter E box of the alpha-SMA gene, which was disrupted by c-myb antibodies and competed with by c-myb cognate DNA. Treatment with pentoxifylline or metabolite 5 prevented the molecular abnormalities characteristic of stellate cell activation induced by CCl4. These results suggest that induction of c-myb plays an important role in the in vivo activation of stellate cells. Pentoxifylline blocks stellate cell activation in vivo independently of its inhibitory effects on phosphodiesterases by interfering with the oxidative stress cascade and the activation of NF-kappa B and c-myb.
Full Text
https://journals.physiology.org/doi/full/10.1152/ajpgi.1997.273.5.G1094#
DOI
10.1152/ajpgi.1997.273.5.G1094
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Kwan Sik(이관식) ORCID logo https://orcid.org/0000-0002-3672-1198
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/177254
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