4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells.
OBJECTIVE
4-Hydroxynonenal (HNE) is a putative pro-fibrogenic product of oxidative stress able to elicit apoptosis and cytotoxicity in several cell types. This study has been performed to evaluate its 'in vivo' levels in injured liver and whether HNE may induce apoptosis and/or affect selected phenotypic responses in activated human hepatic stellate cells (HSC/MF).


RESULTS
During the development of acute liver injury induced by CCl(4), liver tissue HNE levels were in the range 0.5-10 microM, as shown by high performance liquid chromatography analysis. Cultured human HSC/MF, developed cytotoxicity only if exposed to very high HNE concentrations (25-50 microM) without any sign of induction of classic, caspase-dependent apoptosis, as assessed by evaluating morphology and biochemical parameters of cell death. HNE, at non-cytotoxic doses, up-regulated procollagen type I and tissue inhibitor of metalloproteinases-1 gene expression and/or protein synthesis without significantly affecting chemotaxis (wound healing and haptotaxis assay), matrix metalloproteinases 1 and 2 mRNA expression and activity as well as basal DNA synthesis.


CONCLUSIONS
HNE, at concentrations compatible with those detected in vivo, does not elicit HSC/MF classic apoptosis but, rather, may act as a potent pro-fibrogenic stimulus for the expression of genes involved in excess extracellular matrix deposition and proposed as survival signals for HSC/MF.
Zamara
Elena
E
Dipartimento di Medicina e Oncologia Sperimentale, Università di Torino, Corso Raffaello 30, 10125 Turin, Italy.
Novo
Erica
E
Marra
Fabio
F
Gentilini
Alessandra
A
Romanelli
Roberto Giulio
RG
Caligiuri
Alessandra
A
Robino
Gaia
G
Tamagno
Elena
E
Aragno
Manuela
M
Danni
Oliviero
O
Autelli
Riccardo
R
Colombatto
Sebastiano
S
Dianzani
Mario Umberto
MU
Pinzani
Massimo
M
Parola
Maurizio
M
D000199:Actins / Q000378:metabolism; D000208:Acute Disease; D000447:Aldehydes / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride; D016923:Cell Death; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D003599:Cytoskeleton / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000209:etiology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009994:Osmolar Concentration; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D000199:Actins; D000447:Aldehydes; D002251:Carbon Tetrachloride; C027576:4-hydroxy-2-nonenal